Process for preparing btk inhibitors

ABSTRACT

Methods for preparing the Bruton&#39;s Tyrosine Kinase (“BTK”) inhibitor compound 2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided. Methods for preparing tricyclic lactam compounds are also provided.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a continuation of Ser. No. 17/102,086, filed Nov.23, 2020, which is a divisional of U.S. patent application Ser. No.16/460,889, filed Jul. 2, 2019, issued as U.S. Pat. No. 10,882,864 onJan. 5, 2021, which is a divisional of U.S. patent application Ser. No.15/841,828, filed Dec. 14, 2017, issued as U.S. Pat. No. 10,385,058 onAug. 20, 2019, which claims priority to U.S. Provisional PatentApplication No. 62/434,569, filed Dec. 15, 2016, the contents of each ofwhich are hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The field of the invention relates generally to methods of preparing theBruton's Tyrosine Kinase (“BTK”) inhibitor compound2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one.The field of the invention further relates generally to methods ofpreparing tricyclic lactam compounds.

The BTK inhibitor compound2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-oneof the following structure:

is known from U.S. publication US 2013/0116235 A1 as a BTK inhibitorthat is useful for the treatment of a disease or disorder selected fromimmune disorders, cancer, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders. US 2013/0116235 is incorporated herein by reference in itsentirety. Alternative names for2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-onecan be used, but the shown chemical structure controls. The US2013/0116235 publication a useful method for preparing2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one,but the method requires chromatographic purification and a low yield wasachieved.

The US 2013/0116235 publication further discloses a useful five-stepprocess for the preparation of tricyclic lactam compounds used asintermediates in the preparation of2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-oneand having the structure:

In the final step, the above-reference tricyclic lactam compound isgenerated by ring closure from the following compound:

The multistep process requires two chromatographic purification stepsand the overall yield based on the starting material was low.

A need therefore exists for improved method for preparing2-{3′-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4′]bipyridinyl-2′-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-oneand intermediate compounds therefore.

BRIEF DESCRIPTION OF THE INVENTION

One aspect of the invention is directed to a method of preparingcompound 200, stereoisomers thereof, geometric isomers thereof,tautomers thereof, and salts thereof:

The method comprises forming a first reaction mixture comprisingcompound 170, compound 181, a palladium catalyst, a solvent systemcomprising water, and a base, wherein the ratio of solvent volume tocompound 170 weight in the reaction mixture is less than 20:1 liters perkg, the equivalent ratio of compound 181 to compound 170 is greater than1:1, and the equivalent ratio of the palladium catalyst to compound 170is from about 0.005:1 to about 0.05:1.

The method further comprises reacting the first reaction mixture to forma first reaction product mixture comprising compound 190 according tothe following scheme:

Compound 190 is isolated from the first reaction mixture.

A second reaction mixture is formed comprising compound 190, a reducingagent, a base and a solvent. The second reaction mixture is reacted toreduce the aldehyde moiety of compound 190 and form a second reactionproduct mixture comprising compound 200. Compound 200 is isolated fromthe reaction product mixture.

The yield of compound 190 is at least 50% based on compound 170, and theyield of compound 200 is at least 50% based on compound 190.

Another aspect of the invention is directed to a method for preparing atricyclic lactam of formula 400, stereoisomers thereof, geometricisomers thereof, tautomers thereof, and salts thereof:

The method comprises forming a reaction mixture comprising an organicsolvent, an organic base, and the compounds of formulas 300 and 310:

The reaction mixture is reacted to form a reaction product mixturecomprising the tricyclic lactam of formula 400. R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are independently selectedfrom H, and C₁₋₆ alkyl. R⁵ is selected from H, C₁₋₆ alkyl, cycloalkyl,aryl, substituted aryl, benzyl, substituted benzyl, heteroaryl,substituted heteroaryl. p is 1, 2, 3 or 4; and q is 1, 2, 3 or 4.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a method for the preparation of compounds 170, 182, 190 and200.

FIG. 2 shows a method for the preparation of compounds 170 and 182, andanother method for the preparation of compounds 190 and 200.

FIG. 3 shows a method for the preparation of compounds 70, 90, 40, 154,153, 140, 141 and 180.

FIG. 4 shows a method for the preparation of compounds 70, 90, 40, 154,153, and another method for the preparation of compounds 140, 141 and180.

FIG. 5 shows a method for the preparation of compounds 40, 154, 151, 70,90, 161, 160 and 180.

FIG. 6 shows a method for the preparation of compounds 40, 154, 155,156, 141 and 180.

FIG. 7 shows a method for the preparation of compounds 31, 157, 156,141, and 180.

FIG. 8 shows a method for the preparation of compounds 120, 130 and 160.

FIG. 9 shows a method for the preparation of compounds 120, 121, 130 and160.

FIG. 10 shows a method for the preparation of compounds 122, 130 and160.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application. including but not limited to defined terms, termusage, described techniques, or the like, this application controls.Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are incorporated by reference in theirentirety.

Definitions

When indicating the number of substituents, the term “one or more”refers to the range from one substituent to the highest possible numberof substitution, i.e. replacement of one hydrogen up to replacement ofall hydrogens by substituents. The term “substituent” denotes an atom ora group of atoms replacing a hydrogen atom on the parent molecule. Theterm “substituted” denotes that a specified group bears one or moresubstituents. Where any group may carry multiple substituents and avariety of possible substituents is provided, the substituents areindependently selected and need not to be the same. The term“unsubstituted” means that the specified group bears no substituents.The term “optionally substituted” means that the specified group isunsubstituted or substituted by one or more substituents, independentlychosen from the group of possible substituents. When indicating themm1ber of substituents, the term “one or more” means from onesubstituent to the highest possible number of substitution, i.e.replacement of one hydrogen up to replacement of all hydrogens bysubstituents.

As used herein, “alkyl” refers to a monovalent linear or branchedsaturated hydrocarbon moiety, consisting solely of carbon and hydrogenatoms, having from one to twelve carbon atoms. “Lower alkyl” refers toan alkyl group of one to six carbon atoms, i.e. C₁-C₆alkyl. Examples ofalkyl groups include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl,dodecyl, and the like.

As used herein, “alkylene” refers to a linear saturated divalenthydrocarbon radical of one to six carbon atoms or a branched saturateddivalent hydrocarbon radical of three to six carbon atoms, e.g.,methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene,butylene, pentylene, and the like.

As used herein, “cycloalkyl” refers to a monovalent saturatedcarbocyclic moiety consisting of mono- or bicyclic rings. Particularcycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl canoptionally be substituted as defined herein. Examples of cycloalkylmoieties include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl (i.e., “Cy”), cycloheptyl, and the like,including partially unsaturated (cycloalkenyl) derivatives thereof.

As used herein, “aryl” refers to a monovalent aromatic hydrocarbonradical of 6-20 carbon atoms (C₆-C₂₀). Aryl includes bicyclic radicalscomprising an aromatic ring fused to a saturated, partially unsaturatedring, or aromatic carbocyclic ring. Typical aryl groups include, but arenot limited to, radicals derived from benzene (phenyl), substitutedbenzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl,1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Arylgroups are optionally substituted independently with one or moresubstituents described herein.

As used herein, “arylalkyl” and “aralkyl”, which may be usedinterchangeably, refer to a radical-R_(a)R_(b) where R_(a) is analkylene group and R_(b) is an aryl group as defined herein; e.g.,phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

As used herein, “heteroaryl” refers a monovalent aromatic radical of 5-,6-, or 7-membered rings, and includes fused ring systems (at least oneof which is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups areoptionally substituted independently with one or more substituentsdescribed herein.

As used herein, “alkoxy” refers to a moiety of the structure —OR,wherein R is an alkyl moiety as defined herein. Examples of alkoxymoieties include, but are not limited to, methoxy, ethoxy, isopropoxy,and the like.

As used herein, “haloalkyl” refers to an alkyl as defined herein inwhich one or more hydrogen atoms have been replaced with the same or adifferent halogen. Exemplary haloalkyls include —CH₂Cl, —CH₂CF₃,—CH₂CCl₃, —CF₃, CHF₂, and the like.

As used herein, “halogen” refers to chlorine, fluorine, bromine andiodine.

As used herein, “amino” refers to a moiety of the structure —NRR′wherein R and R′ each hydrogen, “monoalkylamino” refers to such astructure where one of R and R′ is hydrogen and the other of R and R′ isalkyl, and “dialkylamino” refers to such a structure where each of R andR′ is alkyl.

As used herein, “optionally substituted” as used herein refers to amoiety that may be unsubstituted or substituted with specific groups.Examples of substituents include, but are not limited to hydroxy, alkyl,alkoxy, halo, haloalkyl, oxo, amino, monoalkylamino, or dialkylamino.

As used herein, “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

As used herein, “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

As used herein, “diastereomer” refers to a stereoisomer with two or morecenters of chirality and whose molecules are not mirror images of oneanother.

Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

As used herein, “enantiomers” refer to two stereoisomers of a compoundwhich are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or Rand S, are used to denote the absoluteconfiguration of the molecule about its chiral center (s). The prefixesd and l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity. Enantiomers may be separated from a racemic mixture bya chiral separation method, such as supercritical fluid chromatography(SFC). Assignment of configuration at chiral centers in separatedenantiomers may be tentative, while stereochemical determination awaits,such as x-ray crystallographic data.

As used herein, the terms “tautomer” and “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “salt” refers to both acid addition salts andbase addition salts. “Acid addition salt” refers to salts formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, carbonic acid, phosphoric acid, and organic acidsselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asfomlic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, asparticacid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid,cinnanlic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid mesylate, ethanesulfonic acid, p-toluenesulfonicacid, and salicyclic acid. “Base addition salt” refers to salts formedwith an organic or inorganic base.

As used herein an “inorganic base” generally includes sodium, potassium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, andaluminum salts. Non-limiting examples include phosphates such asdipotassium monohydrogen phosphate, potassium dihydrogen phosphate,tripotassium phosphate, disodium monohydrogen phosphate, sodiumdihydrogen phosphate, trisodium phosphate, diammonium monohydrogenphosphate, ammonium dihydrogen phosphate and triammonium phosphate;acetates such as potassium acetate, sodium acetate and ammonium acetate;formates such as potassium formate and sodium formate; carbonates suchas potassium carbonate, sodium carbonate, potassium hydrogen carbonateand sodium hydrogen carbonate; and alkali metal hydroxides such aslithium hydroxide, sodium hydroxide and potassium hydroxide. Theinorganic bases may be used singly, or in combination of two or morekinds thereof.

As used herein, an “organic base” generally includes primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such aspyridine, isopropylamine, trimethylamine, diethylamine, triethylamine,triethanolamine, diisopropylamine, ethanolamine, 2-diethylaminoethanol,trimethylamine, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, and polyamine resins.

As used herein, “non-polar solvent” refers to a solvent withoutsignificant partial charges on any atoms or a solvent where polar bondsare arranged in such a way that the effect of their partial chargescancel out. Non-limiting examples of non-polar solvents include pentane,hexane, heptane, cyclocpentane, cyclohexane, benzene, toluene,1,4-dioxane, dichloromethane (“DCM”), methyl tert-butyl ether (“MTBE”),chloroform, carbon tetrachloride, and diethyl ether.

As used herein, an “aprotic solvent” refers to a solvent that does notdonate hydrogen. Aprotic solvents typically have a labile hydrogen boundto an oxygen atom or to a nitrogen atom. As used herein, “polar aproticsolvent” refers to a solvent having high dielectric constants and highdipole movements and that lack an acidic hydrogen. Non-limiting examplesof polar aprotic solvents include tetrahydrofuran (“THF”), methyltetrahydrofuran (“Me-THF”), ethyl acetate (“EA”), acetone,dimethylformamide (“DMF”), acetonitrile (“ACN”), petroleum ether,N-methyl-2-pyrrolidone (“NMP”), and dimethyl sulfoxide.

As used herein, “polar protic solvent” refers to a solvent having alabile hydrogen bound to an oxygen atom or a nitrogen atom. Non-limitingexamples of polar protic solvents include formic acid, n-butanol,i-propanol, n-propanol, ethanol, methanol, acetic acid and water.

As used herein, a “low boiling solvent” refers to a solvent having aboiling point of less than about 45° C. Non-limiting examples of lowboiling solvents include dichloromethane, diethyl ether and pentane.

As used herein, a palladium catalyst refers to any palladium catalystthat affects the rate and conversion of a chemical substrate compound toa product compound as a commercially acceptable yield and conversion. Insome aspects, the palladium catalyzed reactions described herein requirea zero valent palladium species (Pd(0)). Exemplary catalytically active(Pd(0)) species may be applied directly (e.g. as commercial Pd(0)complexes such as Pd(PPh₃)₄, Pd(PCy₃)₂, Pd(PtBu₃)₂ or similar Pd(O)complexes), or may be formed from a palladium source in combinationeither with a phosphine ligand and/or a base (e.g., KOtBu, KOH, NaOAc,K₃PO₄, K₂CO₃, Hunig's base, NEt₃, NPr₃). In some aspects, the palladiumsource is selected from the following non-exclusive listing: [PdCl(X)]₂(X=allyl, cinnamyl, crotyl, . . . ), [Pd(X)PR₃] (R=alkyl or aryl),[Pd(X)(Y)] (Y=cyclopentadienyl, p-cymyl, . . . ), Pd(dba)₂, Pd₂(dba)₃,Pd(OAc)₂, PdZ₂ (Z═Cl, Br, I), Pd₂Z₂(PR₃)₂, and Pd(TFA)₂. In someaspects, the catalytic palladium species is a palladium source selectedfrom the following non-excusive listing: [Pd(allyl)Cl]₂, Pd(MeCN)₂Cl₂,Pd(benzonitrile)₂Cl₂, Pd(dba)₂, Pd(OAc)₂, PdCl₂, PdBr₂, Pd(TFA)₂,Pd(MeCN)₄(BF₄)₂, Pd₂(dba)₃, Pd(PCy₃)₂Cl₂, Pd(acac)₂, and Pd(PPh₃)₄. Insome such aspects, the palladium source is Pd₂(dba)₃ or Pd(OAc)₂. Insome such aspects, the palladium source is Pd(PCy₃)₂. In some otheraspects, the catalytic palladium species can be formed in situ from apalladium source, such as described above, and a ligand.

Non-limiting examples of ligands include DPPF, DTPBF, BINAP, DPPE, DPPP,DCPE, RuPhos, SPhos, APhos (amphos), CPhos, XPhos, t-BuXPhos,Me₄t-BuXPhos, neopentyl(t-Bu)₂P, (t-Bu)₂PMe, (t-Bu)₂PPh, PCy₃, PPh₃,XantPhos, and N-XantPhos. In some aspects, the ligand is an arylphosphate. In some aspects, the ligand is BINAP, XantPhos, or XPhos. Inparticular aspects, the ligand is Xantphos(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or Xphos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) of the followingstructures:

In some other aspects, the catalytic is a preformed catalyst.Non-limiting examples of preformed catalysts include Pd(dppf)Cl₂,Pd(dppe)Cl₂, Pd(PCy₃)₂Cl₂, bis(triethylphospine)palladium(II) chloride,Pd(t-Bu₃P)₂Cl₂, Pd[P(o-tol)₃]2Cl₂, Pd(PPh₃)₂Cl₂, Pd(OAc)₂(PPh₃)₂, andPd(CH₃CN)₂Cl₂. In some such aspects, the preformed catalyst isPd(dppf)Cl₂. In some further aspects, the catalyst source or preformedcatalyst may complex with a solvent such as dichloromethane, chloroformor acetonitrile. Non-limiting examples of such complexes includePd(dppf)Cl₂·DCM, Pd₂(dba)₃·CHCl₃ and Pd(PPh₃)₂Cl₂·ACN.

As used herein, a borylation reagent refers to any borylation reagentcapable of cross-coupling with an aryl halide to form an aryl boronate.Examples of borylation reagents include, without limitation,tetrahydroxyboron, catecholborane,4,4,5,5-tetramethyl-1,3,2-dioxaborolane,4,6,6-trimethyl-1,3,2-dioxaborinane, diisopropylamine borane,bis(neopentyl glycolato)diboron, bis(catecholato)diboron, bis(hexyleneglycolato)diboron, bis(pinacolato)diboron,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine,bis(2,4-dimethylpentane-2,4-glycolato)diboron, phenyl boronic acid,diisopropoxy methyl borane, and methyl boronic acid.

As used herein “reducing agent” refers to a compound that donates anelectron. Non-limiting examples of reducing agents include sodiumborohydride, potassium borohydride, sodium bis(2-methoxyethoxy)aluminumhydride, sodium bisulfite, sodium hydrogensulfite, sodium hydrosulfite,sodium tetrahydroborate, potassium tetrahydroborate, sodiumtriacetoxyborohydride, trichlorosilane, triphenylphosphite,triethylsilane, trimethylphosphine, triphenylphosphine, diborane,diethoxymethylsilane, diisobutylaluminum hydride,diisopropylaminoborane, lithium aluminum hydride, and lithiumtriethylborohydride.

As used herein “protecting group” refers to group used for protection ofremote functionality (e.g., primary or secondary amine) ofintermediates. The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups include acetyltrifiuoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

As used herein “equivalent ratio” refers to a mole ratio.

As used herein, “predominant” and “predominantly” refer to greater than50%, at least 75%, at least 90%, at least 95%, at least 99% or at least99.9% on any of a weight, volume, molar, v/w %, w/w %, w/v % or v/v %basis.

Compounds of the present disclosure may be separated, isolated andpurified by the following non-exclusive methods and combinationsthereof. In some methods, the compounds may be isolated and/or purifiedby forming a suspended solid thereof in a liquid carrier phase bymethods such as salt formation, crystallization or precipitation (suchas by solvent concentration, solvent exchange, pH adjustment and/ortemperature adjustment). In some other purification methods, solutionsof the compounds may be contacted with a source of carbon (such ascharcoal), diatomaceous earth and/or a chromatography resin, to removeimpurities. Two phase solid-liquid mixtures comprising (i) solidcompounds of the present disclosure and a liquid carrier phase or (ii)compounds of the present disclosure in solution in a liquid carrierphase in combination with suspended solids (e.g., charcoal, diatomaceousearth or resin) may be separated by filtration or centrifugation.Isolated solids may be optionally washed to remove additional impurities(in the case of solid product compound) or soluble product (e.g., in thecase of a product solution). In some methods, the compounds of thepresent disclosure may be isolated and/or purified by liquid-liquidextraction and phase separation. Phase separation may be suitably donegravimetrically or by liquid-liquid centrifugation. In some methods, thecompounds of the disclosure may be isolated and/or purified bychromatographic methods such as ion exchange chromatography or affinitychromatography. In one such method, the compounds may be isolated and/orpurified by preparative HPLC. In some methods, the compounds may beisolated and/or purified by distillation (e.g., fractionaldistillation). In some other methods, compounds of the presentdisclosure may be isolated and/or purified by ultrafiltration. In any ofthe various aspects, solid compounds of the present disclosure mayoptionally be dried, such as using vacuum dryers or fluidized beddryers. Any of the separation, isolation and purification methods may beused in combination. For instance, and without limitation, compounds ofthe present disclosure may be isolated and purified by extraction,solvent exchange, crystallization, and drying. In some othernon-limiting aspects, compounds of the present disclosure may beprecipitated or crystallized, isolated, dissolved, precipitated orcrystallized, isolated, and dried, where two or more dissolution andcrystallization iterations are possible. In some other non-limitingaspects, the compounds of the present disclosure may be isolated bysolvent exchange and fractional distillation.

Preparation of Compound 200

In some aspects of the present invention, compound 200, stereoisomersthereof, geometric isomers thereof, tautomers thereof, and saltsthereof, may be prepared from compounds 170 and 181 according to thefollowing two step reaction scheme:

In a first step, compound 190 comprises is prepared from a firstreaction mixture comprising compound 170, compound 181, a palladiumcatalyst, a solvent system comprising water, and a base, and reactingthe first reaction mixture to form a first reaction product mixturecomprising compound 190. In some aspects, compound 190 is isolated fromthe first reaction product mixture. In a second step, compound 200 isprepared from a second reaction mixture comprising compound 190, areducing agent, a base and a solvent, and reacting the second reactionmixture to reduce the aldehyde moiety of compound 190 and form a secondreaction product mixture comprising compound 200. Compound 200 isoptionally isolated from the second reaction product mixture.

In the first reaction mixture, the equivalent ratio of compound 181 tocompound 170 is greater than 1:1. The palladium catalyst in the firstreaction mixture is a palladium catalyst as described elsewhere herein.In some aspects, the palladium catalyst is Pd(dppf)Cl₂·DCM. In someaspects, the palladium catalyst is Pd(dppf)Cl₂. The equivalent ratio ofthe palladium catalyst to compound 170 is about 0.005:1, about 0.01:1,about 0.02:1, about 0.03:1, about 0.04:1, about 0.05:1, about 0.06:1,about 0.07:1 or about 0.08:1, and ranges thereof, such as from about0.005:1 to about 0.08:1, from about 0.005:1 to about 0.05:1, or fromabout 0.005:1 to about 0.02:1. In some aspects, the first reactionmixture base is an inorganic base. In some particular aspects, the baseis K₃PO₄ or K₂HPO₄. In some aspects, the first reaction mixture solventsystem comprises water and a polar aprotic solvent. The volume ratio ofwater to polar aprotic solvent is about 0.05:1, about 0.1:1, about0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1,about 0.8:1 or about 0.9:1, and ranges thereof, such as from about0.05:1 to about 0.9:1 from about 0.05:1 to about 0.5:1, or from about0.1:1 to about 0.4:1. In some particular aspects, the solvent systemcomprises water and THF. In some aspects, the ratio of the solventsystem volume in the first reaction mixture to compound 170 weight maybe less than about 20:1 L/kg, about 5:1 L/kg, about 10:1 L/kg, about15:1 L/kg, about 20:1 L/kg, about 25:1 L/kg, or about 30:1 L/kg, andranges thereof, such as from about 5:1 to about 30:1 L/kg or from about5:1 to about 20:1 L/kg.

The reaction temperature for forming compound 190 is suitably about 40°C., about 45° C., about 50° C., about 55° C., or about 60° C. Thereaction may be deemed complete when the area % concentration by HPLC ofcompound 170 is less than 2, less than 1, less than 0.5 or less than0.1. The reaction time to completion may be 2 hours, 4 hours, 8 hours,12 hours, 16 hours, 20 hours or 24 hours.

In some aspects of the invention, compound 190 may be purified. In somesuch aspects, the temperature of the first reaction product mixture maybe adjusted from about 10° C. to about 35° C. or from about 15° C. toabout 30° C. and combined with agitation with aqueousN-acetyl-L-cysteine having a N-acetyl-L-cysteine concentration of about3 wt. %, about 6 wt. % or about 9 wt. %, and ranges thereof, such asfrom about 3 wt. % to about 9 wt. %. The equivalent ratio ofN-acetyl-L-cysteine to compound 190 may be from about 0.1:1, about 0.3:1or about 0.5:1, and ranges thereof, such as from about 0.01:1 to about0.5:1. The ratio of aqueous N-acetyl-L-cysteine volume to compound 190weight may be about 1 L/kg, about 2 L/kg or about 3 L/kg, and rangesthereof, such as from about 1 L/kg to about 3 l/kg. An aqueous layer isseparated and an organic layer comprising compound 190 is collected. Insome aspects, the upper layer may be optionally combined with agitationwith citric acid solution having a citric acid concentration of about 3wt. %, about 5 wt. % or about 7 wt. %, and ranges thereof, such as fromabout 3 wt. % to about 7 wt. %, wherein the ratio of the citric acidsolution volume to compound 190 weight may be about 0.5 L/kg, about 1l/kg, about 1.5 L/kg or about 2 L/kg, and ranges thereof, such as fromabout 0.5 L/kg to about 2 L/kg. It is believed that the dimer impuritypredominantly partitions to the citric acid wash. The organic layer maybe further optionally combined with a salt solution (e.g. NaCl) having asalt content of from about 15 wt. % to about 35 wt. %, wherein the ratioof the salt solution volume to compound 190 weight may be about 0.5L/kg, about 1 l/kg, or about 1.5 L/kg, and ranges thereof, such as fromabout 0.5 L/kg to about 1.5 L/kg. An aqueous layer is separated and anorganic layer comprising compound 190 is collected. The organic layermay optionally be washed one or more additional times with the saltsolution at a ratio of the salt solution volume to compound 190 weightof from about 0.5 L/kg to about 4 L/kg. Optionally, a base, such asaqueous 60 wt. % K₂HPO₄ in a volume to compound 190 weight ratio of fromabout 0.5 L/kg to about 1.5 L/kg, may be included in the final saltwash. After the final salt wash, an aqueous layer is separated and anorganic layer comprising compound 190 is collected.

Compound 190 may optionally be isolated from the first reaction productmixture or from the organic layer comprising compound 190 from thepurification step by combining the first reaction product mixture or theupper layer comprising compound 190 with a solvent having a boilingpoint of less than about 80° C. and having a polarity similar to thesolvent in the first reaction product mixture or the organic layercomprising compound 190. In some aspects, the solvent is THF. The volumemay be reduced by vacuum distillation, and the reduced volume comprisingcompound 190 may be diluted with the solvent (e.g., THF) to a totalsolvent volume of from about 8 to about 12 L solvent per kg of compound190 to produce a diluted solution of compound 190. The diluted admixturemay optionally be combined and treated with activated carbon followed byfiltration to generate a filtered solution of compound 190. The volumeof the solution of purified compound 190 may be reduced by distillationto a reduced volume of from about 3 to about 7 L solvent per kg ofcompound 190. The THF dilution and distillation step may be repeated oneor more times. From about 3 to about 7 L of ethanol per kg of compound190 may be combined with the reduced volume and may thereafter bedistilled to a reduced volume of from about 3 to about 7 L solvent perkg of compound 190. The ethanol addition and distillation step may berepeated one or more times. Ethanol may be added to the reduced volumeto a concentration of from about 8 to about 12 L solvent per kg ofcompound 190 to produce a diluted mixture of compound 190. The dilutedmixture of compound 190 may be cooled, such as to less than 25° C., tocrystalize purified compound 190 from the cooled and diluted mixture.The purified compound 190 crystals may be collected, such as byfiltration or centrifugation, and dried to yield purified dry compound190 crystals.

The yield of compound 190 based on compound 170 is at least 50%, atleast 60%, at least 70%, at least 80% or at least 90%, and the purity ofcompound 190 is at least 99 area % by HPLC or at least 99.5 area % byHPLC.

In the second reaction mixture, in some aspects, the solvent is selectedfrom C₁₋₆ alcohols, ethers and cyclic ethers. In some particularaspects, the solvent in the second reaction mixture is selected fromTHF, methyl tert-butyl ether, and 2-Me-THF. The ratio of solvent volumeto compound 190 weight may be about 2:1 L/kg, about 3:1 L/kg, about 4:1L/kg, about 5:1 L/kg, about 6:1 L/kg, about 7:1 L/kg, about 8:1 L/kg,about 9:1 L kg, about 10:1 L/kg, and ranges thereof, such as from about2:1 to about 10:1 L/kg, or from about 4:1 to about 8:1 L/kg. In someaspects, the base in the second reaction mixture is an inorganic base,such as an alkali hydroxide. In one such aspect, the base is sodiumhydroxide. The equivalent ratio of base to compound 190 is about 0.1:1,about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about0.7:1, about 0.8:1, or about 0.9:1, and ranges thereof, such as fromabout 0.1:1 to about 0.9:1 or from about 0.3:1 to about 0.7:1. In any ofthe various aspects, the reducing agent is as described elsewhereherein. In some particular aspects, the reducing agent is sodiumborohydride. The equivalent ratio of the reducing agent to compound 190is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1,about 0.6:1, about 0.7:1, about 0.8:1, or about 0.9:1, and rangesthereof, such as from about 0.1:1 to about 0.9:1 or from about 0.2:1 toabout 0.8:1. In any of the various aspects, the boronate is generatedfrom a borylation agent as described elsewhere herein. In one suchaspect, the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of thestructure:

The reaction temperature for forming compound 200 is suitably about 10°C., about 15° C., about 20° C., about 25° C., or about 30° C. Thereaction may be deemed complete when the area % concentration by HPLC ofcompound 200 is less than 2, less than 1, less than 0.5 or less than0.1. In some aspects, the reaction time to completion may be 0.5 hours,1 hour, 2 hours, 4 hours, 6 hours, or more. The yield of compound 200 isat least 60%, at least 70%, at least 80%, or at least 85%, and thepurity of compound 200 is at least 99 area % or at least 99.5 area % byHPLC.

Compound 200 may be isolated from the second reaction product mixture.In some aspects, compound 200 may be isolated by admixing the secondreaction product mixture with monopotassium phosphate solution in avolume ratio to compound 200 weight of from about 0.5 L to about 2 L ofabout 10 percent by weight to about 25 percent by weight aqueousmonopotassium phosphate solution per kg of compound 200. An aqueouslayer is separated and an organic layer comprising compound 200 insolution is collected. The organic layer comprising compound 200 may befiltered. The filtrate may be distilled to a volume of from about 2 toabout 4 L/kg of compound 200. A suitable solvent, such as methanol, maybe added to the distilled filtrate to a total volume of from about 6 toabout 8 L/kg of compound 200. In some aspects, from about 0.2 to about0.8 percent by weight compound 200 seed crystals may be added to form amixture. The mixture is distilled to reduce the volume by at least 1L/kg of compound 200. The distilled mixture of compound 200 may becooled, such as to less than 20° C., to crystalize compound 200 from thecooled mixture. Compound 200 crystals may be collected and dried.

In some aspects, the purified compound 200 crystals may berecrystallized in a purifcation step. In some such aspects, compound 200is combined with ethanol at a ratio of ethanol volume to compound 200weight of from about 4 L/kg to about 10 L/kg or from about 6 L/kg toabout 8 L/kg and with toluene at a ratio of toluene volume to compound200 weight of from about 1 L/kg to about 5 L/kg or from about 1.5 L/kgto about 3.5 L/kg and with agitation. The mixture may be heated, such asto from about 65 to about 85° C., with agitation and held until asolution is obtained. The solution may be then cooled, such as to fromabout 60 to about 70° C., and combined with seed crystals, such as fromabout 0.5 wt. % to about 3 wt. % or from about 0.5 wt. % to about 1.5wt. % compound 200 seed crystals, to form a slurry. Ethanol may becombined with the slurry at a ratio of ethanol volume to compound 200weight of from about 5 L/kg to about 25 L/kg or from about 10 L/kg toabout 20 L/kg. The slurry may be cooled, such as to from about −5 toabout 15° C., and held for at least 2 hours, at least 4 hours, or atleast 8 hours to crystallize compound 200. The crystals may becollected, such as by filtration or centrifugation, and washed withethanol. The washed crystals may be dried under vacuum with a N₂ purgeat from about 40 to about 60° C. for at least 4 hours, at least 8 hours,at least 12 hours, or at least 20 hours to produce purified compound200.

In some aspects of the present invention, compound 170 may be preparedfrom compounds 100 and 160 according to the following reaction scheme:

The method for preparing compound 170 comprises forming a reactionmixture comprising compound 160, a stoichiometric excess of compound100, a palladium catalyst and a catalyst ligand, a base and a polaraprotic solvent. The reaction mixture is reacted to form a reactionproduct mixture comprising compound 170. Compound 170 may optionally beisolated from the reaction mixture.

The equivalent ratio of compound 100 to compound 160 in the reactionmixture is greater than 1:1, about 1.05:1, about 1.1:1, about 1.2:1,about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1 or about 1.7:1, andranges thereof, such as between 1:1 and 1.7:1, from about 1.05:1 toabout 1.5:1 or from about 1.05:1 to about 1.2:1. In some aspects,compound 160 is prepared as disclosed elsewhere herein. The palladiumcatalyst and catalyst ligand are as described elsewhere herein. In someaspects, the catalyst is Pd(OAc)₂ and the ligand is DPPF. The polaraprotic solvent is as described elsewhere herein. In some aspects, thesolvent is THF. The ratio of solvent volume to compound 160 weight inthe reaction mixture may be about 2:1 L/kg, about 5:1 v L/kg, about 10:1L/kg, about 15:1 L/kg, about 20:1 L/kg, about 25:1 L/kg, or about 30:1L/kg, and ranges thereof, such as from about 2:1 to about 30:1 L/kg,from about 5:1 to about 20:1 L/kg, or from about 5:1 to about 15:1 L/kg.In some aspects, the concentration of compound 160 in the reactionmixture is about 0.1 mol/L, about 0.2 mol/L, about 0.3 mol/L, about 0.4mol/L, about 0.5 mol/L, about 0.75 mol/L, about 1 mol/L, and rangesthereof, such as from about 0.1 mol/L to about 1 mol/L, or from about0.2 to about 0.5 mol/L. The equivalent ratio of catalyst to compound 160is from about 0.01:1, about 0.02:1 about 0.03:1, about 0.04:1, or about0.05:1, and ranges thereof, such as from about 0.01:1 to about 0.05:1 orfrom about 0.01:1 to about 0.03:1. The equivalent ratio of the ligand tothe catalyst is from about 1.2:1, about 1.5:1, about 2:1, about 2.5:1 orabout 3:1, and ranges thereof, such as from about 1.2:1 to about 3:1 orfrom about 1.5:1 to about 2.5:1. In some aspects, the base is aninorganic base as described elsewhere herein. In some particularaspects, the base is potassium carbonate. The equivalent ratio of thebase to compound 160 is suitably greater than 1:1, about 1.2:1, about1.5:1 about 1.8:1 or about 2:1, and ranges thereof, such as between 1:1and 2:1, or from about 1.2:1 to about 1.8:1.

The reaction may be run under a N₂ blanket and/or with N₂ purging. Thereaction may be done at reflux temperature, typically between about 60°C. and about 80° C. The reaction may be deemed complete when the area %concentration by HPLC of compound 160 is less than 3, less than 2, lessthan 1 or less than 0.5. In some aspects, the reaction time tocompletion may be 2 hours, 6 hours, 10 hours, 14 hours, 18 hours, 22hours, or more.

Compound 170 may be isolated from the reaction product mixture. In someaspects, water may be combined with the reaction product mixture at aratio of water volume to compound 160 weight of about 2:1, about 5:1,about 10:1, about 15:1 or about 20:1, and ranges thereof, such as fromabout 2:1 to about 20:1 or from about 2:1 to about 10:1. The temperaturemay be reduced to induce crystallization of compound 170 and form asuspension of solid compound 170. The temperature may be from about 5°C. to about 30° C., or from about 15° C. to about 25° C. The temperaturemay be maintained for at least 1 hour, at least 2 hours or at least 3hours. Solid compound 170 may be isolated from the reaction mixture,such as by filtration or centrifugation. Isolated compound 170 mayoptionally be dried. In some drying aspects, drying is done under apartial vacuum with a N₂ purge at a temperature of from about 15° C. toabout 40° C., or from about 15° C. to about 30° C. for at least 2 hours,at least 3 hours or at least 4 hours.

The yield of compound 170 based on compound 160 is at least 80%, atleast 85% or at least 90%. The purity of compound 170 is at least 95area %, at least 98 area % or at least 99 area % by HPLC.

In some aspects of the present invention, compound 100 may be preparedfrom compound 95 according to the following two step reaction scheme:

In the first step, a first reaction mixture comprising compound 95,n-butyl lithium, an organic base, and a polar aprotic solvent, is formedand reacted to form a first reaction product mixture comprising compound96. In the second step, a second reaction product mixture is formed byadmixing the first reaction product mixture with a polar aproticsolvent. The second reaction mixture is reacted to form a secondreaction product mixture comprising compound 100. Compound 100 mayoptionally be isolated from the second reaction product mixture.

In some aspects, the first reaction mixture comprises a polar aproticsolvent as described elsewhere herein. In some aspects, the polaraprotic solvent is THF. The solvent volume to compound 95 weight in thefirst reaction mixture is about 2:1 L/kg, about 3:1 L/kg, about 4:1L/kg, about 5:1 L/kg, about 6:1 L/kg, about 7:1 L/kg, about 8:1 L/kg,about 9:1 L/kg, or about 10:1 L/kg, and ranges thereof, such as fromabout 2:1 to about 10:1 L/kg, from about 3:1 to about 10:1 L/kg, or fromabout 4:1 to about 6:1 L/kg. The mole ratio of n-butyl lithium tocompound 95 is greater than 1:1, about 1.2:1, about 1.4:1, about 1.6:1,about 1.8:1, about 2:1, and ranges thereof, such as between 1:1 and 2:1,or from about 1.2:1 to about 1.6:1. The n-butyl lithium may be asolution of n-butyl lithium in hexane, such as a 2.5 molar solution. Theorganic base is as defined elsewhere herein. In some aspects, theorganic base is diisopropylamine. The mole ratio of the organic base tocompound 95 is about 1.1:1, about 1.2:1 about 1.4:1, about 1.6:1 about1.8:1 or about 2:1, and ranges thereof, such as from about 1.1:1 toabout 2:1, from about 1.2:1 to about 2:1, or from about 1.4:1 to about1.8:1. The reaction temperature for generation of the first reactionproduct mixture is greater than −35° C., about −30° C., about −25° C.,about −20° C., about −15° C., or about −10° C., and ranges thereof, suchas between −35° C. and about −10° C., or from about −30° C. to about−15° C.

In some aspects, the second reaction mixture comprises additional polaraprotic solvent. In some aspects, the polar aprotic solvent is DMF. Insuch aspects, the volume of the additional polar aprotic solvent tocompound 95 weight in the second reaction mixture is about 2:1 L/kg,about 3:1 L/kg, about 4:1 L/kg, about 5:1 L/kg, about 6:1 L/kg, about7:1 L/kg, about 8:1 L/kg, about 9:1 L/kg, or about 10:1 L/kg, and rangesthereof, such as from about 2:1 to about 10:1 L/kg, or from about 3:1 toabout 7:1 L/kg. In such aspects, the mole ratio of the additional polaraprotic solvent to compound 95 is from about 1.1:1 to about 2:1, or fromabout 1.3:1 to about 1.5:1. The reaction temperature for generation ofthe first reaction product mixture is greater than −50° C., about −45°C., about −40° C., about −35° C., about −30° C., about −25° C., about−20° C., about −15° C., or about −10° C., and ranges thereof, such asbetween −50° C. and −10° C., or between −30° C. and −15° C. The secondreaction product mixture may be quenched with an aqueous mineral acidsolution, such as a 10 wt. % to 25 wt. % solution of HCl wherein theequivalent ratio of acid to compound 100 may be from about 2:1 to about8:1, or from about 4:1 to about 6:1.

Compound 100 may be prepared in either a batch or a continuous scheme.In a continuous scheme, solution A (n-BuLi in hexane as describedelsewhere herein), and solution B (diisopropylamine in THF) may betransferred through a mixer and into a first reactor to form a firstreaction product mixture. In some aspects, the residence time in thefirst reactor is suitably from about 10 to about 60 seconds or fromabout 20 to about 30 seconds and the reaction temperature is greaterthan −35° C. as described elsewhere herein. The first reaction productmixture and solution C (compound 95 in solvent as described elsewhereherein) may be transferred through a mixer and into a second reactor toform a second reaction product mixture comprising a solution oflithiated 2,4-dichloropyridine. In some aspects, the residence time inthe second reactor is suitably from about 10 to about 60 seconds or fromabout 20 to about 30 seconds and the reaction temperature is greaterthan −35° C. as described elsewhere herein. The second reaction productmixture and solution D (DMF as described elsewhere herein) may betransferred through a mixer and into a third tubular reactor to form athird reaction product mixture comprising compound 100. In some aspects,the residence time in the third reactor is suitably from about 10 toabout 60 seconds or form about 20 to about 30 seconds and the reactiontemperature is greater than −35° C. as described elsewhere herein. Thethird reaction product mixture may be collected in a quench reactor atfrom about 0 to about 20° C. and combined with an aqueous quenchsolution (such as an HCl quench solution as described elsewhere herein).Suitable continuous reactors include, for instance, tubular reactors andcontinuous stirred tank reactors.

Compound 100 may be optionally isolated from the second reaction productmixture.

In one such isolation aspect, compound 100 may be extracted from aquenched second reaction product mixture comprising water at atemperature of from about 5° C. to about 30° C. by admixing the quenchedsecond reaction product mixture with ethyl acetate, and separating anethyl acetate phase comprising compound 100. The ratio of ethyl acetatevolume to compound 95 weight may be about 1:1 L/kg, about 2:1 L/kg,about 3:1 L/kg, about 4:1 L/kg, or about 5:1 L/kg. One or moreextractions may be done. The collected ethyl acetate extractions may bewashed with a brine solution and dried over sodium sulfate. The ethylacetate extractions may be concentrated under reduced pressure, such asto a volume to compound 95 weight ratio of from about 2:1 to about 4:1L/kg. Petroleum ether at a w/w % ratio to compound 95 of from about 3:1to about 12:1 or from about 5:1 to about 9:1 may be added to the ethylacetate and agitated at less than 25° C. for a time sufficient to form aslurry containing solid compound 100. Solid compound 100 may isolated,such as by filtration or centrifugation, and dried under vacuum at fromabout 30° C. to about 50° C. to yield solid compound 100.

In another such isolation aspect, the quenched reaction product mixturecomprising compound 100 may be heated to from about 10 to about 35° C.followed by phase separation. The organic and aqueous layers may becollected and the aqueous layer may be mixed and extracted with anon-polar solvent, followed by phase separation. The w/w ratio of thenon-polar solvent to compound 100 is suitably from about 3:1 to about12:1 or from about 6:1 to about 10:1. One or more extraction steps maybe done. In some aspects the non-polar solvent is toluene. The organiclayers may be combined, and optionally washed with brine and water. Theorganic layers may be concentrated and cooled to from about 30 to about50° C. A linear non-polar solvent (e.g., heptane) may be added whilemaintaining the temperature to from about 30 to about 50° C. The w/wratio of the linear non-polar solvent to compound 100 is suitably fromabout 5:1 to about 20:1 or from about 10:1 to about 14:1. A resultingslurry comprising solid compound 100 may be cooled and aged for fromabout 1 to about 3 hours at from about −20 to about 0° C. Compound 100may isolated, such as by filtration or centrifugation, and dried underpartial or full vacuum. In some aspects, the drying temperature may beless than 40° C.

In yet another such isolation aspect, the quenched reaction productmixture comprising compound 100 may be heated to from about 10 to about35° C. followed by phase separation. The organic and aqueous layers maybe collected and the aqueous layer may be mixed and extracted with anon-polar solvent (e.g., toluene), followed by phase separation. The w/wratio of the non-polar solvent to compound 100 is suitably from about3:1 to about 12:1 or from about 6:1 to about 10:1. One or moreextraction steps may be done. In some aspects the non-polar solvent istoluene. The combined organic layers are then washed with brine,followed by an aqueous solution of sodium bicarbonate, followed by afinal wash with water. In some embodiments, the wash with brine is donewith about 2-3 equivalent volumes of brine. In some embodiments, theaqueous sodium bicarbonate solution has a concentration of about 5%NaHCO₃ in water. In some embodiments, the wash with brine is done withabout 5 equivalent volumes of 4.8% NaHCO₃. In some embodiments, thefinal wash with water is done with about 1 equivalent volume of water.The organic layers may be concentrated and cooled to from about 30 toabout 50° C. A linear non-polar solvent (e.g., heptane) may be addedwhile maintaining the temperature to from about 30 to about 50° C. Thew/w ratio of the linear non-polar solvent to compound 100 is suitablyfrom about 5:1 to about 20:1 or from about 10:1 to about 14:1. Aresulting slurry comprising solid compound 100 may be cooled and agedfor from about 1 to about 3 hours at from about −20 to about 0° C.Compound 100 may isolated, such as by filtration or centrifugation, anddried under partial or full vacuum. In some aspects, the dryingtemperature may be less than 40° C.

The yield of compound 100 is at least 70%, at least 80%, at least 85% orat least 87%. The purity of compound 100 is at least 90 area %, at least95 area %, or at least 99.5 area % by HPLC.

In some aspects of the present invention, compound 181 may be preparedfrom compound 180 according to the following reaction scheme:

The method for preparing compound 181 comprises forming a reactionmixture comprising compound 180, a palladium catalyst, a catalystligand, a borylation reagent, an alkali metal acetate salt, and a polaraprotic solvent. The reaction mixture is reacted to form a reactionproduct mixture comprising compound 181. Compound 181 is optionallyisolated from the reaction product mixture.

The palladium catalyst and the catalyst ligand are as describedelsewhere herein. In some aspects, the palladium catalyst is Pd₂(dba)₃and the catalyst ligand is an aryl phosphate ligand. In some suchaspects, the aryl phosphate ligand is XPhos. The equivalent ratio ofpalladium catalyst to compound 180 is about 0.001:1, about 0.002:1,about 0.003:1, about 0.004:1, or about 0.005:1, and ranges thereof, suchas from 0.001:1 to about 0.005:1. The equivalent ratio of catalystligand to catalyst is about 1.3:1, about 1.5:1, about 1.7:1, about1.9:1, about 2.5:1 or about 3:1, and ranges thereof, such as from about1.3:1 to about 3 or from about 1.5:1 to about 2.5:1. The borylationreagent is as described elsewhere herein. The solvent is a polar aproticsolvent as described elsewhere herein. In some aspects, the polaraprotic solvent is THF. The ratio of solvent volume to compound 180weight is about 3:1 L/kg, about 5:1 L/kg, about 10:1 L/kg, about 20:1L/kg, or about 25:1 L/kg, and ranges thereof, such as from about 3:1 toabout 25:1 L/kg, from about 5:1 to about 20:1 L/kg, or from about 5:1 toabout 15:1 L/kg. In some aspects, the reaction mixture comprises acompound 180 concentration of about 0.1 moles/L, about 0.2 moles/L,about 0.3 moles/L, about 0.4 moles/L, or about 0.5 moles/L, and rangesthereof, such as from about 0.1 to about 0.5 moles/L. The equivalentratio of the alkali metal acetate salt to compound 180 is greater than1:1. In some aspects, the alkali metal acetate salt is potassiumacetate. In some aspects, the borylation reagent isbis(pinacolato)diboron and the boronate is4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The equivalent ratio ofborylation reagent to compound 180 is greater than 1:1, about 1.2:1,about 1.5:1 or about 2:1, and ranges thereof, such as between 1:1 and2:1. In some aspects, the alkali metal acetate salt is potassiumacetate. In some aspects, the borylation reagent isbis(pinacolato)diboron and the boronate is4,4,5,5-tetramethyl-1,3,2-dioxaborolane. In such aspects, boronatecompound 181 is the species of compound 182:

The reaction for forming compound 181 or 182 may be done with N₂ purgingand/or a N₂ blanket. The reaction is may be done at reflux temperature,typically between about 60° C. and about 80° C. The reaction may bedeemed complete when the area % concentration by HPLC of compound 160 isless than 1, less than 0.5, or less than 0.1. In some aspects, thereaction time to completion may be about 6 hours, about 12 hours, about18 hours, about 24 hours, or more.

In some aspects, compound 181 or 182 may be isolated from the reactionproduct mixture. In some such aspects, the reaction product mixture maybe combined with water at a ratio of water volume to compound 181 or 182weight of about 2 L/kg, about 3 L/kg, about 4 L/kg or about 5 L/kg, andratios thereof, such as from about 1 to about 5 L/kg or from about 2 toabout 4 L/kg. An aqueous layer is separated and an organic layercomprising compound 181 or 182 in solution is collected. The organiclayer may be distilled to a reduced volume at a ratio of volume tocompound 181 or 182 weight of about 2 L/kg, about 3 L/kg, about 4 L/kgor about 5 L/kg, and ranges thereof, such as from about 2 to about 5L/kg. Distillation is suitably vacuum distillation, such as forinstance, at a temperature of at least 40° C. Alternatively, thedistillation may be performed at atmospheric pressure. The reducedvolume comprising compound 181 or 182 may be diluted with a polaraprotic solvent, such as THF, in a ratio of solvent volume to compound181 or 182 weight of about from about 5 L/kg to about 8 L/kg, thediluted mixture is optionally filtered, and the diluted mixture may bedistillated to a reduced volume of from about 2 to about 4 L per kg ofcompound 181 or 182. The polar aprotic solvent dilution and distillationstep may be repeated one or more times. The reduced volume may becombined a non-polar solvent, such as MTBE, at a ratio of non-polarsolvent volume to compound 181 or 182 weight of about 5 L/kg, about 10L/kg, about 15 L/kg or about 20 L/kg, and ranges thereof, such as fromabout 5 to about 20 L/kg or from about 5 to about 15 L/kg. The admixturemay be cooled to from about 0 to about 15° C. to form compound 181 or182 as a solid dispersion. Solid compound 181 or 182 may be collected,such as by filtration or centrifugation, and dried to form solidcompound 181 or 182.

Alternatively, after completion of the reaction to form compound 181 or182, inorganic salts are filtered off at 60-65° C. The filtrate iscooled to 40-45° C. and filtered over charcoal. The volume of thefiltrate is then reduced at atmospheric pressure. The reduced volume maybe combined with a non-polar solvent, such as MTBE, at a ratio ofnon-polar solvent volume to compound 181 or 182 weight of about 5 L/kg,about 10 L/kg, about 15 L/kg or about 20 L/kg, and ranges thereof, suchas from about 5 to about 20 L/kg or from about 5 to about 15 L/kg.

The yield of compound 181 or 182 based on compound 180 is at least 80%,at least 85% or at least 90%. The purity of compound 181 or 182 is atleast 95 area %, at least 98 area % or at least 99 area % by HPLC.

In some aspects of the present invention, compound 180 may be preparedfrom compounds 90 and 141 according to the following reaction scheme:

The method for preparing compound 180 comprises forming a reactionmixture comprising compound 141, compound 90, a palladium catalyst andan aryl phosphate catalyst ligand, a base, and an aprotic solvent. Thereaction mixture is reacted to form a reaction product mixturecomprising compound 180. Compound 180 is optionally isolated from thereaction product mixture.

The reaction mixture comprises approximately equimolar amounts ofcompounds 90 and 141. The aprotic solvent is as described elsewhereherein. In some aspects, the aprotic solvent is selected from THF,toluene, Me-THF, 1,4-dioxane, and combinations thereof. In someparticular aspects, the solvent is 1,4-dioxane. The concentration ofcompound 141 in the solvent in the reaction mixture is about 2 w/w %, 4w/w %, about 6 w/w %, about 8 w/w %, about 10 w/w %, about 12 w/w %, orabout 14 w/w %, and ranges thereof, such as from about 2 to about 14 w/w% or from about 6 to about 10 w/w %. In some aspects, the source ofcompound 141 is solid compound 141 or a residue comprising compound 141.In some other aspects, the source of compound 141 is a solution ofcompound 141 in the solvent, wherein the solution comprises from about 3to about 15 percent by weight compound 141 and less than 0.15 percent byweight methanol. The palladium catalyst and catalyst ligand are asdescribed elsewhere herein. In some aspects, the palladium catalyst isPd₂(dba)₃ and the catalyst ligand is Xantphos. The equivalent ratio ofthe palladium catalyst to compound 141 is from about 0.005:1 to about0.05:1, or from about 0.01:1 to about 0.03:1. The equivalent ratio ofthe catalyst ligand to the catalyst is from about 1.2:1 to about 3:1 orfrom about 1.5:1 to about 2.5:1. In some aspects, the base is aninorganic base as described elsewhere herein. In some such aspects, thebase is potassium carbonate or tripotassium phosphate. The mole ratio ofthe base to compound 141 is from about 1.5:1 to about 3:1.

The reaction for forming compound 180 may be done with N₂ purging and/ora N₂ blanket. The reaction may be done at reflux temperature, typicallybetween about 80° C. and about 120° C. The reaction may be deemedcomplete when the area % concentration by HPLC of compound 180 is lessthan 2, less than 1, less than 0.5, or less than 0.1. In some aspects,the reaction time to completion may be about 6 hours, about 12 hours,about 18 hours, about 24 hours, about 30 hours, or more.

In some aspects, compound 180 may be isolated from the reaction productmixture. In some such aspects, the reaction product mixture may becooled to from about 50° C. to about 85° C. and filtered. The filtratemay optionally be washed with aprotic solvent (e.g., 1,4-dioxane) andthe wash may be combined with the filtrate. The filtrate may beconcentrated to almost dryness. In some aspects, the concentration maybe done in a vacuum at a temperature of from about 45 to about 75° C. toform a residue of compound 180. The residue may be optionally purifiedby combining the residue with methanol to form a slurry of compound 180at a ratio of methanol volume to compound 180 weight of about 2:1 L/kg,about 3:1 L/kg, about 4:1 L/kg, about 5:1 L/kg or about 6:1 L/kg, andranges thereof, such as from about 2:1 to about 6:1 L/kg or from about2:1 to about 4:1 L/kg. The slurry may be cooled to from about −5 toabout 10° C. and stirred for at least 1 hour. Crude compound 180 solidsmay be collected, such as by filtration or centrifugation, and the solidmay be optionally washed with cold methanol. The crude solids may bedried under vacuum, such as for instance, at a temperature of from about45 to about 75° C. for at least 0.5 hours. The dried crude solids may becombined with a aprotic solvent (e.g., 1,4-dioxane) as a w/w ratio ofsolvent to compound 180 of from about 1.1:1 to about 2:1 or from about1.2:1 to about 1.7:1 and the resulting mixture may be heated to refluxtemperature and stirred for at least 0.1 hour at reflux temperature.i-propanol may be added to the heated mixture at a ratio of i-propanolvolume to compound 180 weight of from about 1.5:1 to about 6:1 L/kg orfrom about 2.5:1 to about 5:1 L/kg. The resulting mixture may be cooledto from about 10 to about 30° C. and stirred at that temperature to forma slurry comprising solid compound 180. Solid compound 180 may becollected, such as by filtration or centrifugation, and the collectedsolids may be optionally washed with i-propanol. Compound 180 solids maybe dried under vacuum, such as at a temperature from about 50 to about80° C., for at least 2 hours.

The yield of compound 180 is at least 60%, at least 70%, or at least80%. The purity of compound 180 is at least 95 area %, at least 98 area%, or at least 99 area % by HPLC.

In some aspects of the present invention, compound 141 may be preparedfrom compound 140 according to the following reaction scheme:

The method for preparing compound 141 comprises forming a reactionmixture comprising compound 140, a palladium on carbon catalyst,hydrogen, and a solvent selected from methanol, ethanol, isopropanol,dioxane, toluene, and combinations thereof. The reaction mixture isreacted to form a reaction product mixture comprising compound 141.

The ratio of the solvent volume to compound 140 weight is about 3:1L/kg, about 5:1 L/kg, about 10:1 L/kg, about 15:1 L/kg, or about 20:1L/kg, and range thereof, such as from about 3:1 to about 20:1 L/kg, fromabout 3:1 to about 10:1 L/kg, or from about 4:1 to about 6:1 L/kg. Insome aspects, the solvent is methanol. The weight ratio of the catalystto compound 140 is from about 10 w/w %, about 15 w/w %, about 20 w/w %,about 25 w/w % or about 30 w/w % and ranges thereof, such as from about10 to about 30 w/w %, or from about 10 to about 25 w/w %.

The reaction for forming compound 141 may be done with N₂ purging priorto introducing H₂. The reaction is typically done at a temperature offrom about 35° C. to about 65° C. or form about 45° C. to about 55° C.In some aspects, the reaction time to completion may be about 6 hours,about 12 hours, about 18 hours, about 24 hours, or more. The reactionmay be deemed complete when the area % concentration by HPLC of compound140 is less than 2, less than 1, less than 0.5, or less than 0.1. Thereaction product mixture is filtered and the filtrate comprises compound141 in solution.

In some aspects, compound 141 may be isolated from the reaction productmixture as a residue by concentration of the filtrate to almost dryness.In some aspects, the concentration may be done in a vacuum at atemperature below 60° C. In some optional aspects, the compound 141residue may be combined with an aprotic solvent such as THF, toluene,Me-THF or 1,4-dioxane followed by concentration to almost dryness. Insome aspects, the concentration may be done in a vacuum at a temperaturebelow 60° C. to form a residue. The ratio of solvent volume to compound141 weight in such aspects is about 3:1 L/kg, about 5:1 L/kg, about 7:1L/kg or about 9:1 L/kg and ranges thereof, such as from about 3:1 toabout 9:1 L/kg or from about 3:1 to about 7:1 L/kg. In some aspects, thesolvent is 1,4-dioxane. The residue may optionally be combined with theaprotic solvent at a ratio of solvent volume to compound 141 weight ofabout 5:1 L/kg, about 10:1 L/kg or about 15:1 L/kg or about 20:1 L/kgand ranges thereof, such as from about 5:1 to about 20:1 L/kg or fromabout 5:1 to about 15:1 L/kg. In some such aspects, the finalconcentration of compound 141 in the aprotic solvent (e.g., 1,4-dioxane)is from about 5 to about 15 percent by weight.

The yield of compound 141 is at least 90% or at least 95%.

In some aspects of the present invention, compound 140 may be preparedfrom compounds 20 and 153 according to the following reaction scheme:

The method for preparing compound 140 comprises forming a reactionmixture comprising compound 153, compound 20, a solvent, NaBH(OAc)₃, andacetic acid.

In some aspects, the reaction mixture further comprises a drying agent.The reaction mixture is reacted to form a reaction product mixturecomprising compound 140. Compound 140 may optionally be isolated fromthe reaction product mixture.

The solvent is selected from THF, Me-THF, DCM, and combinations thereof.In some aspects, the solvent is DCM. In some aspects the source ofcompound 153 is a solution of compound 153 in the solvent. In any of thevarious aspects, the concentration of compound 153 in the solvent isfrom about 2 to about 10 percent by weight. The equivalent ratio ofcompound 20 to compound 153 is from about 1.3:1 to about 1.9:1. Theequivalent ratio of acetic acid to compound 153 is from about 1.1:1 toabout 3:1. The equivalent ratio of NaBH(OAc)₃ to compound 153 is greaterthan 1.5:1. In some aspects, the drying agent is magnesium sulfatewherein the equivalent ratio of magnesium sulfate to compound 153 isfrom about 0.3:1 to about 0.6:1.

The reaction for forming compound 140 may be done with N₂ purging and/orwith an N₂ blanket. The reaction is typically done at a temperature offrom about 30° C. to about 50° C. In some aspects, the reaction time tocompletion may be about 0.5 hours, about 1 hour, about 2 hours, about 4hours, or more. The reaction may be deemed complete when the area %concentration by HPLC of compound 153 is less than 2, less than 1, lessthan 0.5, or less than 0.1.

In some aspects, compound 140 may be isolated from the reaction productmixture. In such aspects, the reaction product mixture may be combinedwith water at a ratio of water volume to compound 140 weight of about3:1 L/kg about 5:1 L/kg, about 7:1 L/kg, about 9:1 L/kg or about 11:1L/kg and ranges thereof, such as from about 3:1 to about 11:1 L/kg orfrom about 5:1 to about 9:1 L/kg. The phases are separated to form anaqueous phase and a first organic phase comprising compound 140 insolution. The aqueous phase may be extracted with the solvent (e.g.,DCM) at ratio of solvent volume to compound 140 weight of from about 1L/kg to about 5 L/kg or from about 2 L/kg to about 4 L/kg, and thephases separated to form a second organic phase comprising compound 140in solution in the solvent. The first and second organic phases may becombined and washed with water. In some aspects, the volume of washwater is approximately the same as the volume of solvent used to formthe second organic phase. The washed combined organic phases may beoptionally washed at least one more time with water. The washed organicphases comprising compound 140 in solution may be dried with a dryingagent (e.g., magnesium sulfate), and then filtered. The filtrate may beoptionally further washed with solvent (e.g., DCM). The filtrate may beconcentrated to almost dryness under vacuum at a temperature below 50°C. to form compound 140 residue. Optionally, the residue may be combinedwith a non-polar solvent to form a mixture having a ratio of solventvolume to compound 140 weight of from about 1.5:1 L/kg to about 4:1L/kg. In some aspects, the non-polar solvent is petroleum ether. Themixture may be stirred at from about 5 to about 35° C. for a timesufficient to form a solution of compound 140. The solution may then befiltered and concentrated to dryness under a vacuum at a temperature offrom about 40 to about 70° C. to form solid compound 140.

The yield of compound 140 is at least 85% or at least 90%. The purity ofcompound 140 is at least 95%, at least 98% or at least 98.5% by HPLC.

In some aspects of the invention, compound 153 may be prepared fromcompound 152 according to the following reaction scheme:

The method for preparing compound 153 comprises forming a reactionmixture comprising compound 152 having a protecting group moiety, PG,hydrochloric acid, and a solvent comprising water. The reaction mixtureis reacted to form a reaction product mixture comprising deprotectedcompound 152. Compound 152 may optionally be isolated from the reactionproduct mixture. In some aspects, PG is BOC.

The reaction for forming compound 153 may be done with N₂ purging and/orwith an N₂ blanket. The reaction is typically done at a temperature offrom about 40 to about 70° C. or from about 50 to about 60° C. In someaspects, the reaction time to completion may be about 1 hour, about 2hour, about 3 hours, about 4 hours, or more. The reaction may be deemedcomplete when the area % concentration by HPLC of compound 152 is lessthan 2, less than 1, less than 0.5, or less than 0.1.

In some aspects, compound 153 may be isolated from the reaction productmixture. In such aspects, the reaction product mixture may be cooled,such as for instance to from about 10 to about 30° C., and the reactionmixture may be extracted with a non-polar solvent as described elsewhereherein (e.g., DCM) at a ratio of solvent volume to compound 153 weightof from about 3:1 L/kg to about 11:1 L/kg or from about 5:1 L/kg toabout 9 L/kg. The aqueous phase may be collected and the pH thereofadjusted to greater than 11 with an aqueous strong inorganic base, forinstance, about 30% NaOH. The pH-adjusted aqueous phase may be extractedwith a non-polar solvent (e.g., DCM) at a ratio of solvent volume tocompound 153 weight of from about 5:1 L/kg to about 20:1 L/kg or fromabout 8:1 L/kg to about 15:1 L/kg. A second aqueous phase extractionwith the non-polar solvent may be done. The organic phases are combinedand may be washed at least once with water in a volume generallyconsistent with the volume of each non-polar solvent extraction. Thecombined washed organic phases may then be dried with a drying agent(e.g., MgSO₄) and filtered. The filtrate comprises compound 153 insolution at a concentration of about 2 w/w %, about 4 w/w %, about 6 w/w% or about 8 w/w %, and ranges thereof, such as from about 2 to about 8w/w % or from about 2 to about 6 w/w %. In some aspects, solid compound153 may be obtained by solvent evaporation under vacuum. In some otheraspects, the solution of compound 153 may be used directly for thepreparation of compound 140. The yield of compound 153 is at least 80%or at least 90%.

In some particular aspects of the invention, compound 200 is preparedaccording to the method depicted in FIG. 1 . In some other particularaspects of the invention, compound 200 is prepared according to themethod depicted in FIG. 2 .

In some particular aspects of the invention depicted in FIGS. 3 and 4and as generally described elsewhere herein: (1) compound 60 andN-bromosuccinimide are reacted to form compound 70; (2) compound 70 andmethyl-p-tosylate are reacted to form compound 90; (3) compound 30 anddi-tert-butyl dicarbonate are reacted to form Boc-protected compound 40;(4) compounds 50 and 40 are reacted in the presence of palladiumcatalyst and a catalyst ligand to form compound 154; (5) compound 154 isde-protected to form compound 153; (6) compound 153 and compound 20 arereacted to form compound 140; (7) compound 140 is reduced byhydrogenation in the presence of a palladium on carbon catalyst to formcompound 141; and (8) compound 141 is reacted with compound 90 in thepresence of a palladium catalyst and a catalyst ligand to form compound180.

In some other particular aspects of the invention, compound 180 isprepared according to the method depicted in FIG. 5 . A reaction mixturecomprising compound 30, di-tert-butyl dicarbonate, and a suitablesolvent is formed, and the reaction mixture is reacted at about 25° C.for about 18 hours to form a reaction product mixture comprisingBoc-protected compound 40 at a yield of from about 69% to about 77%. Areaction mixture comprising compound 51, compound 40, a suitablesolvent, K₃PO₄, Pd(OAc)₂ catalyst and BINAP ligand is formed, and thereaction mixture is reacted at about 90° C. for about 15 hours to form areaction product mixture comprising BOC-protected compound 154 at ayield of from about 80% to about 84%. A reaction mixture comprisingcompound 154, sodium sulfide hydrate, and a solvent system comprisingmethanol and water is formed, and the reaction mixture is reacted atfrom about 60° C. to about 75° C. for about 2 hours to form a reactionproduct comprising compound 151 at a yield of from about 94% to about97%. A reaction mixture comprising compound 60, N-bromosuccinimide andacetonitrile is formed, and the reaction mixture is reacted at fromabout 25° C. to about 55° C. for about 2 hours to form a reactionproduct mixture comprising compound 70 at a yield of from about 69% toabout 74%. A reaction mixture comprising compound 70, methyl-p-tosylate,K₂CO₃ and DMF is formed, and the reaction mixture is reacted to form areaction product mixture comprising compound 90 at a yield of from about75% to about 80%. A reaction mixture comprising compound 151, compound90, Pd₂(dba)₃ catalyst, a Xantphos catalyst ligand, and dioxane isformed, and the reaction mixture is reacted at about 100° C. for about15 hours to form a reaction product mixture comprising Boc-protectedcompound 161 at a yield of from about 70% to about 75%. Compound 161 isde-protected with about 7.2% HCl followed by neutralization with about20% NaOH to produce a reaction product mixture comprising compound 160at a yield of from about 95 to about 99%. A reaction mixture comprisingcompound 160, compound 20, NaBH(OAc)3, acetic acid, magnesium sulfate,and DCM is formed, and the reaction mixture is reacted at about 40° C.for about 2 hours to form a reaction product mixture comprising compound180 at a yield of from about 70% to about 75%. The overall yield basedon compound 51 is about 38%.

In some other particular aspects of the invention, compound 180 isprepared according to the method depicted in FIG. 6 . A reaction mixturecomprising compound 60, N-bromosuccinimide and acetonitrile is formed,and the reaction mixture is reacted at from about 25° C. to about 55° C.for about 2 hours to form a reaction product mixture comprising compound70 at a yield of from about 69% to about 74%. A reaction mixturecomprising compound 70, methyl-p-tosylate, K₂CO₃ and DMF is formed, andthe reaction mixture is reacted to form a reaction product mixturecomprising compound 90 at a yield of from about 75% to about 80%. Areaction mixture comprising compound 30, di-tert-butyl dicarbonate, anda suitable solvent is formed, and the reaction mixture is reacted atabout 25° C. for about 18 hours to form a reaction product mixturecomprising Boc-protected compound 40 at a yield of from about 69% toabout 77%. A reaction mixture comprising compound 50, compound 40,dioxane, K₃PO₄, Pd(OAc)₂ catalyst and BINAP ligand is formed. In thereaction mixture, the concentration of compound 50 in dioxane is about10 w/w %, the equivalent ratio of K₃PO₄ to compound 50 is about 2, theequivalent ratio of Pd(OAc)₂ catalyst to compound 50 is about 0.012:1,and the equivalent ratio of Pd(OAc)₂ catalyst to BINAP ligand is about1:1. The reaction mixture is reacted at from about 95° C. to about forabout 105° C. for about 15 hours to form a reaction product mixturecomprising BOC-protected compound 154 at a yield of about 79%. Areaction mixture comprising compound 154, methanol, 10% palladium oncarbon catalyst and hydrogen is formed. In the reaction mixture, theratio of methanol volume to compound 154 weight is about 5:1, and theweight ratio of the palladium on carbon catalyst to compound 154 isabout 0.05:1. The hydrogenation reaction mixture is reacted at fromabout 45° C. to about 55° C. for about 2 hours to form a reactionproduct mixture comprising compound 155 at a yield of about 97%.Compound 155 is de-protected with HCl in a solvent system comprisingethyl acetate at a temperature of from about 25° C. to about for about35° C. for from about 7 hours to about 10 hours to form de-protectedcompound 156 at a yield of about 93%. A reaction mixture comprisingcompound 156, compound 20, NaBH(OAc)₃, acetic acid, and DCM is formed,and the reaction mixture is reacted to form a reaction product mixturecomprising compound 141 at a yield of about 100% wherein the purity ofcompound 141 is from about 85 area % to about 90 area % by HPLC. Areaction mixture comprising compound 141, compound 90, Pd₂(dba)₃catalyst, Xantphos catalyst ligand, K₃PO₄, and dioxane was formed, andthe reaction mixture was reacted at about 100° C. for about 15 hours toform compound 180 at a yield of about 47%. The overall yield of compound180 based on compound 50 is about 33%.

In some other particular aspects of the invention, compound 180 isprepared according to the method depicted in FIG. 7 . A reaction mixturecomprising compound 60, N-bromosuccinimide and acetonitrile is formed,and the reaction mixture is reacted at from about 25° C. to about 55° C.for about 2 hours to form a reaction product mixture comprising compound70 at a yield of from about 69% to about 74%. A reaction mixturecomprising compound 70, methyl-p-tosylate, K₂CO₃ and DMF is formed, andthe reaction mixture is reacted to form a reaction product mixturecomprising compound 90 at a yield of from about 75% to about 80%. Areaction mixture comprising compound 30, benzyl chloroformate(“Cbz-Cl”), and a suitable solvent is formed, and the reaction mixtureis reacted to form Cbz-protected compound 31 at a yield of about 87%. Areaction mixture comprising compound 50, compound 31, dioxane, K₃PO₄,Pd(OAc)₂ catalyst and BINAP ligand is formed. In the reaction mixture,the concentration of compound 50 in dioxane is about 10 w/w %, theequivalent ratio of K₃PO₄ to compound 50 is about 2, the equivalentratio of Pd(OAc)₂ catalyst to compound 50 is about 0.012:1, and theequivalent ratio of Pd(OAc)₂ catalyst to BINAP ligand is about 1:1. Thereaction mixture is reacted at from about 95° C. to about 105° C. forabout 15 hours to form a reaction product mixture comprisingCbz-protected compound 157 at a yield of about 77%. A reaction mixturecomprising compound 157, methanol, 10% palladium on carbon catalyst andhydrogen is formed. In the reaction mixture, the ratio of methanolvolume to compound 157 weight is about 5:1, and the weight ratio of thepalladium on carbon catalyst to compound 157 is about 0.05:1. Thehydrogenation reaction mixture is reacted at from about 45° C. to about55° C. for about 2 hours to form a reaction product mixture comprisingde-protected compound 156 at a yield of about 93%. A reaction mixturecomprising compound 156, compound 20, NaBH(OAc)₃, acetic acid, and DCMis formed, and the reaction mixture is reacted to form a reactionproduct mixture comprising compound 141 at a yield of about 100% whereinthe purity of compound 141 is from about 85 area % to about 90 area % byHPLC. A reaction mixture comprising compound 141, compound 90, Pd₂(dba)₃catalyst, Xantphos catalyst ligand, K₃PO₄, and dioxane was formed, andthe reaction mixture was reacted at about 100° C. for about 15 hours toform a reaction product mixture comprising compound 180 at yield ofabout 47%. The overall yield of compound 180 based on compound 50 isabout 33%.

Preparation of Compound 400

In some aspects of the present invention, tricyclic lactam compound 400,stereoisomers thereof, geometric isomers thereof, tautomers thereof, andsalts thereof, may be prepared from compounds 300 and 310 according tothe following reaction scheme:

The method for preparing compound 400 comprises forming a reactionmixture comprising an organic solvent, an organic base, and compounds300 and 310 and reacting the reaction mixture to form a reaction productmixture comprising the tricyclic lactam of compound 400.

R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) areindependently selected from H, and C₁₋₆ alkyl. R⁵ is selected from H,C₁₋₆ alkyl, cycloalkyl, aryl, substituted aryl, benzyl, substitutedbenzyl, heteroaryl, substituted heteroaryl. In some aspects, R^(1a),R^(1b), R^(3a), R^(3b), R^(4a), R^(4b) and R⁵ are H, and R^(2a) andR^(2b) are —CH₃.

The halogen is as described elsewhere herein. In some aspects, thehalogen is Cl or Br. In some other aspects, the halogen is Cl.

p is 1, 2, 3 or 4. In some aspects, p is 1 or 2. q is 1, 2, 3 or 4. Insome aspects, q is 1 or 2. In some other aspects, p is 1 and q is 2.

In some aspects, the tricyclic lactam of compound 400 is speciescompound 160 of the structure:

compound 300 is the species of compound 130 of the structure:

and compound 310 is piperazine-2-one of compound 10:

The organic base is as described elsewhere herein. In some aspects, theorganic base is a tri-C₁₋₆ alkyl amine. In some particular aspects, theorganic base is selected from 4-methylmorpholine andN-ethyldiiopropylamine.

In some aspects, the organic solvent is a polar aprotic solvent asdescribed elsewhere herein. In some particular aspects, the solvent isselected from NMP and DMF.

In some aspects, the concentration of compound 300 in the reactionmixture is from about 0.25 to about 2 moles/L, from about 0.5 to about1.5 moles/L or from about 0.5 to about 1 moles/L. In some aspects, theratio of solvent volume to compound 300 weight is about 1.5:1 L/kg,about 2:1 L/kg, about 3:1 L/kg, about 4 L/kg, about 5:1 L/kg, about 6:1L/kg, about 7:1 L/kg, about 8:1 L/kg, about 9:1 L/kg, or about 10:1L/kg, and ratios thereof, such as from about 1.5:1 to about 10:1 L/kg,from about 2:1 to about 6:1 L/kg, or from about 2:1 to about 4:1 L/kg.The equivalent ratio of the organic base to compound 300 is between 1:1and 2:1, about 1.05:1, about 1.1:1, about 1.2:1, about 1.3:1, about1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1,and ranges thereof, such as from about 1.05:1 to about 1.9:1, or fromabout 1.1:1 to about 1.5:1. In some aspects, compound 300 is present instoichiometric excess over compound 310. In some aspects the equivalentratio of compound 310 to compound 300 is between 0.7:1 and 1:1. In someother aspects, the equivalent ratio of compound 310 to compound 300 isabout 0.7:1, about 0.75:1, about 0.8:1, about 0.85:1, about 0.9:1, about0.95:1 or about 0.99:1, and ranges thereof, such as from about 0.7:1 toabout 0.99:1, or from about 0.75:1 to about 0.95:1.

The reaction for forming a reaction product mixture comprising compound400 may be done with N₂ purging and/or with an N₂ blanket. In someaspects, the organic solvent, organic base and compound 310 are combinedin a reactor with agitation at a temperature of from about 95 to about125° C. or from about 100 to about 120° C. Compound 300 is then added tothe reactor with agitation while maintaining the temperature. In someaspects, compound 300 is in solution in an organic solvent (e.g.,toluene or NMP) as described elsewhere herein. In some aspects, thereaction time to completion may be about 0.25 hours, about 0.5 hours,about 1 hour, about 2 hours, about 3 hours, or more. The reaction may bedeemed complete when the area % concentration by HPLC of compound 300 isless than 5, less than 2, less than 1, less than 0.5, or less than 0.1.

Compound 400 may be isolated from the reaction product mixture. In someisolation aspects, the reaction product mixture may be cooled, such asfor instance to from about 80 to about 95° C. Water may then be combinedwith the reaction product mixture to form a mixture wherein the ratio ofwater volume to compound 300 starting material weight is about 3:1 L/kg,about 5:1 L/kg, about 7:1 L/kg, about 9:1 L/kg, about 11:1 L/kg, about13:1 L/kg, or about 15:1 L/kg, and ranges thereof, such as from about3:1 to about 15:1 L/kg or from about 5:1 to about 10:1 L/kg. The mixtureis cooled to from about 5 to about 30° C. and stirred at temperature forat least 0.5 hours, at least 1 hour, at least 2 hours or at least 3hours to form a slurry comprising solid compound 400. Solid compound 400may be collected, such as by filtration or centrifugation. The solidsmay optionally be subjected to a second water slurry and collectionstep. Acetone may then be combined with the solid compound 400 to form aslurry, for instance at a temperature of from about 10 to about 30° C.,wherein the ratio of acetone volume to compound 300 starting materialweight is about 1.5:1 L/kg, about 2:1 L/kg, about 3:1 L/kg, about 4:1L/kg, about 5:1 L/kg, or about 6:1 L/kg, and ranges thereof, such asfrom about 1.5:1 to about 6:1 L/kg or from about 2:1 to about 4:1 L/kg.The slurry may be agitated for at least 1 hour, at least 2 hours or atleast 3 hours. Solid compound 400 may be isolated, such as by filtrationor centrifugation. The collected solids may be optionally washed withacetone. The solid compound 400 may be dried. In some drying aspects,drying may be done under vacuum at a temperature of from about 25 toabout 50° C.

The yield of compound 400 is at least 50% at least 60% or at least 70%.The purity of compound 400 by HPLC is at least 98 area %, at least 99area %, or at least 99.5 area % by HPLC. In aspects directed totricyclic lactam species compound 160 prepared from compounds 130 and10, impurities are believed to include the following structures:

In some aspects, compound 300 may be prepared from compound 320according to the following reaction scheme:

The method for preparing compound 300 comprises forming a reactionmixture comprising a polar aprotic solvent, a non-polar solvent,phosphorous oxychloride and compound 320. The reaction mixture may bereacted to form a reaction product mixture comprising compound 300.

R^(1a), R^(1b), R^(2a), R^(2b), R^(3a) and R^(3b) are independentlyselected from H, and C₁₋₆ alkyl. In some aspects, R^(1a), R^(1b), R^(3a)and R^(3b) are H, and R^(2a) and R^(2b) are —CH₃. p is 1, 2, 3 or 4. Insome aspects, p is 1 or 2. In other aspects, p is 1.

The polar aprotic solvent is as described elsewhere herein. In someaspects, the polar aprotic solvent is DMF. The non-polar solvent is asdescribed elsewhere herein. In some aspects, the non-polar solvent isDCM.

The reaction mixture may be formed as follows, and the reaction may bedone under a N₂ blanket and/or with a N₂ purge. A reactor is chargedwith the non-polar solvent (e.g., DCM) at a ratio of non-polar solventvolume to compound 320 starting material weight of about 3 L/kg, about 5L/kg, about 7 L/kg, about 9 L/kg, about 11 L/kg, about 13 L/kg, or about15 L/kg, and ranges thereof, such as from about 3 to about 15 L/kg orfrom about 5 to about 11 L/kg, and with the polar aprotic solvent (e.g.,DMF) at an equivalent ratio to compound 320 starting material of about1.5:1, about 2:1, about 2.5:1, about 3:1, about 4:1 or about 5:1, andranges thereof, such as from about 1.5:1 to about 5:1 or from about 2:1to about 3:1. The temperature of the solvent combination is adjusted tofrom about 5 to about 25° C., and POCl₃ is added to the reactor whereinthe equivalent ratio of POCl₃ to compound 320 is about 1.5:1 about 2:1,about 2.25:1, about 2.5:1 or about 3:1, and ranges thereof, such as fromabout 1.5:1 to about 3:1 or from about 2:1 to about 2.25:1. The mixturemay be optionally stirred at temperature for at least 0.5 hours or atleast 1 hour. Compound 320 is then added to the reactor, at atemperature such as from about 5 to about 25° C., to form the reactionmixture. The reaction mixture may then be heated, such as to from about35 to about 55° C., to form a reaction product mixture comprisingcompound 300. In some aspects, the reaction time to completion may be atleast 6 hours, at least 12 hours, at least 18 hours, at least 24 hours,or more. The reaction may be deemed complete when the area %concentration by HPLC of compound 152 is less than 5, less than 2, lessthan 1, less than 0.5, or less than 0.1.

Compound 300 may be optionally purified. In some such aspects, thereaction product mixture may be admixed with water wherein the ratio ofwater volume to compound 320 starting material weight is about 3 L/kg,about 5 L/kg, about 10 L/kg, about 15 L/kg, or about 20 L/kg, and rangesthereof, such as from about 3 to about 20 L/kg, or from about 5 to about15 L/kg. The temperature may suitably be from about 30 to about 50° C.and the admixture may be agitated for at least 0.25 hours, at least 0.5hours or at least 1 hour. The admixture may be cooled, such as to fromabout 15 to about 35° C., and filtered through a filter media, such asdiatomaceous earth. The filtrate may be allowed to separate into anaqueous phase and an organic phase, and the organic phase May becollected and optionally washed with water and brine. The organic phasemay then concentrated, such as for instance to ratio of volume tocompound 320 starting material weight of about 2 L/kg, about 3 L/kg,about 4 L/kg, or about 5 L/kg, and ranges thereof, such as from about 2to about 5 L/kg or from about 2 to about 4 L/kg. An organic solvent(e.g., toluene or NMP) may be combined with the concentrated organicphase at a ratio of organic solvent to compound 320 starting materialweight of about 1 to about 2 L/kg. The volume may be reduced, forinstance, under vacuum and at a temperature below 40° C., to produce asolution of compound 300. In some aspects, the organic solvent is DCMand compound 300 is in solution in DCM.

In some aspects, compound 321 may be prepared from compound 330 whereinR^(1a) and R^(1b) are each independently selected from the groupconsisting of H and C₁₋₆ alkyl, R^(2b) is selected from the groupconsisting of H and C₁₋₆ alkyl according to the following reactionscheme:

The method for preparing compound 321 comprises forming a reactionmixture comprising a polar aprotic solvent, methyl magnesium chloride,copper (I) chloride and compound 330. The reaction mixture is reacted toform a reaction product mixture comprising compound 321.

The polar aprotic solvent is as described elsewhere herein. In someaspects, the polar aprotic solvent is THF.

The reaction mixture may be formed under a N₂ blanket and/or with an N₂purge. In some aspects, the polar aprotic solvent may be charged to areactor and admixed with CuCl and MeMgCl. The ratio of polar aproticsolvent volume to compound 330 starting material weight is about 3 L/kg,about 5 L/kg, about 10 L/kg, about 15 L/kg, or about 20 L/kg, and rangesthereof, such as from about 3 to about 20 L/kg, or from about 5 to about15 L/kg. The equivalent ratio of CuCl to compound 330 starting materialis about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1 or about 0.5:1,and ranges thereof, such as from about 0.1:1 to about 0.5:1 or fromabout 0.1:1 to about 0.3:1. The equivalent ratio of MeMgCl to compound330 starting material is about 0.05:1, about 0.1:1, about 0.015:1 about0.2:1 or about 0.3:1, and ranges thereof, such as from about 0.05:1 toabout 0.3:1 or from about 0.05:1 to about 0.15:1. The mixture is stirredat a temperature of from about −30 to about −10° C. followed by additionof compound 330 to the reactor while maintaining the temperature.Additional MeMgCl is added to the reactor at a temperature of from about−30 to about −10° C. wherein the equivalent ratio of the additionalMeMgCl to compound 330 is about 0.9:1, about 1:1, about 1.1:1 about1.2:1, about 1.3:1, about 1.4:1 or about 1.5:1, and ranges thereof, suchas from about 0.9:1 to about 1.5:1 or from about 1:1 to about 1.2:1. Areaction product mixture comprising compound 321 in solution formed. Insome aspects, the reaction time to completion may be at least 1 hour, atleast 2 hours, at least 4 hours, at least 6 hours, or more. The reactionmay be deemed complete when the area % concentration by HPLC of compound330 is less than 5, less than 2, less than 1, less than 0.5, or lessthan 0.1.

Compound 321 may be isolated from the reaction product mixture. In somesuch aspects, the pH of the reaction product mixture may be adjusted tofrom about 3 to about 4 with an aqueous mineral acid solution, forinstance 3 to 10 w/w % HCl. The resultant aqueous phase and organicphase (e.g., THF) comprising compound 321 in solution may be separated.The aqueous phase may be extracted with a non-polar solvent (e.g., MTBE)at a volume ratio of solvent to compound 330 starting material weight offrom about 2 L/kg to about 10 L/kg or from about 3 L/kg to about 7 L/kg.The organic phases may be combined and washed with aqueous inorganicbase (e.g., NaHCO₃) followed by a brine wash. The washed organic phasemay then be dried with a drying agent, for instance over Na₂SO₄. Thedrying agent may be removed, such as by filtration or centrifugation.The organic phases may be concentrated to a volume ratio to compound 330starting material weight of from about 3 to about 15 L/kg, such as about5 L/kg or about 10 L/kg. Concentration may suitably be done atatmospheric pressure at from about 50 to about 70° C.

In some aspects, compound 321 may be purified by fractional distillationas follows. The combined organic phases or concentrated organic phasesmay be first distilled at a temperature of less than about 60° C. toremove a first (front) fraction predominantly comprising solvent.Distillation may continue to produce a compound 321 product fractioncollected at a temperature of between 60° C. and 90° C. (P≤−0.09 MPa).In such aspects, the yield of compound 321 is at least 40% or at least50% and the HPLC purity of compound 321 is at least 95 area %, at least98 area % or at least 99 area % by HPLC. Distillation may optionally becontinued to remove one or more additional fractions.

In some particular aspects, R^(1a) and R^(1b) are H, R^(2b) is —CH₃, andcompound 321 is the species of compound 120:

andcompound 330 is the species of compound 110:

In some particular aspects, the solvent is THF, the mole ratio of methylmagnesium chloride to compound 110 in the reaction mixture is between1:1 and 2:1, or from about 1.1:1 to about 1.4:1, and the mole ratio ofcopper (I) chloride to compound 110 in the reaction mixture is fromabout 0.1:1 to about 0.5:1, or from about 0.15:1 to about 0.25:1.

In some particular aspects, compounds 130 and 160 may be preparedaccording to the method hereinbefore described and depicted in FIG. 8 .

In some aspects of the invention, compound 320 may be purified by asolid ketone bisulfite adduct route. The purification method comprisesforming a first reaction mixture comprising crude compound 320, anorganic solvent that is not miscible with water (e.g., heptane), and anaqueous solution of sodium bisulfite, and reacting the first reactionmixture to form a first reaction product mixture comprising the solidketone bisulfite adduct of compound 340:

wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a) and R^(3b) are as definedelsewhere herein. In some aspects, compound 340 is the species compound121:

Compound 340 is isolated from the first reaction product mixture. Asecond reaction mixture is formed comprising isolated compound 340,water, a low boiling solvent that is not miscible with water, and sodiumbicarbonate. In some aspects, the solvent is DCM. The second reactionmixture is reacted to form a second reaction product mixture comprisinga first phase comprising the solvent and the predominant amount ofpurified compound 320 is in solution in the first phase, and a secondphase comprising water. The first phase comprising the purified compound320 is separated from the aqueous phase.

In such aspects, the pH of the reaction product mixture comprising crudecompound 320 may be adjusted to less than 5 with an aqueous mineral acidsolution, for instance, aqueous HCl providing about 1.2 to about 1.4equivalent of HCl per equivalent of compound 320.

In the first reaction mixture, the pH-adjusted reaction product mixturemay be combined with a solvent that is not miscible with water (e.g.,hexane) wherein crude compound 320 is soluble in said solvent. In someaspects, the ratio of solvent volume to compound 320 weight of fromabout 5 L/kg to about 25 L/kg, from about 10 L/kg to about 20 L/kg, orfrom about 10 L/kg to about 15 L/kg. The ratio of water volume to thecrude compound 320 weight in the first reaction mixture is from about1:1 L/kg to about 10:1 L/kg, from about 1.5:1 L/kg to about 4:1 L/kg, orfrom about 2:1 L/kg to about 3:1 L/kg. The equivalent ratio of sodiumbisulfite to compound 320 in the first reaction mixture is from about2:1 to about 5:1 or from 3:1 to about 5:1.

The first reaction mixture is formed by combining the pH-adjustedreaction product mixture with the solvent that is not miscible withwater with agitation at a temperature of from about 10 to about 30° C.The resulting admixture is combined with a filter aid (e.g.,diatomaceous earth) and the solids are removed, such as bycentrifugation or filtration. The filtrate is separated to form anorganic phase comprising compound 320 and an aqueous phase. The organicphase is concentrated below at temperature of about 75° C. by reducingthe volume to a ratio of total volume to compound 320 weight of fromabout 1.5 L/kg to about 4 L/kg, or from about 1.5 L/kg to about 2.5L/kg. The reduced volume organic phase is cooled, for instance, to about10 to about 30° C., optionally filtered, and combined with aqueousNaHSO₃ solution providing from about 2 to about 5 equivalents of NaHSO₃per equivalent of compound 320 or from about 3 to about 4.5 equivalentsof NaHSO₃ per equivalent of compound 320 to form a slurry comprisingsolid compound 340. Solid compound 340 is isolated, such as byfiltration or centrifugation, and the collected solids are slurried inthe solvent that is not miscible with water (e.g., hexane). The ratio ofsolvent volume to compound 340 weight is suitably from about 3 L/kg toabout 13 L/kg, or from about 5 L/kg to about 9 L/kg. Solid compound 340is isolated, such as by filtration or centrifugation. The isolatedcompound 340 solids are optionally washed with the low boiling solventvolume that is not miscible with water (e.g., DCM).

The second reaction mixture comprises a ratio of water volume toisolated solid 340 weight of from about 5:1 L/kg to about 15:1 L/kg, orfrom about 7.5:1 L/kg to about 10.5:1 L/kg. The ratio of water volume tothe low boiling solvent volume that is not miscible with water (e.g.,DCM) in the second reaction mixture is from about 1:1 to about 3:1 orfrom about 1.5:1 to about 2.5:1. The ratio of the volume of solvent thatis not miscible with water and compound 340 weight is from about 2 L/kgto about 9 L/kg, from about 3 L/kg to about 7 L/kg, or from about 4 L/kgto about 6 L/kg. The equivalent ratio of sodium bicarbonate to compound340 in the second reaction mixture is between 1:1 and 2:1, or from about1.25:1 to about 1.75:1. In some aspects, the sodium bicarbonate is anaqueous solution of sodium bicarbonate.

The second reaction mixture is formed by combining the compound 340solids with water and with agitation. The low boiling solvent that isnot miscible with water is added and followed by addition of thesolution of sodium bicarbonate to form a second reaction product mixturecomprising compound 320. The resulting admixture may be combined with afiltration aid (e.g., diatomaceous earth) and the solids are removedfrom the admixture, such as by filtration or centrifugation. Thefiltrate or centrifugate is allowed to separate into an organic phaseand an aqueous phase, and the phases are separated and collected. Theaqueous phase may optionally be extracted with the low boiling solventthat is not miscible with water, and the organic phases are combined.The combined organic phase may be washed with brine. The washed combinedorganic phase may be concentrated at a temperature of less than about70° C. to a total volume to compound 320 weight of from about 1.5 L/kgto about 4 L/kg or from about 1.5 L/kg to about 2.5 L/kg and comprisescompound 320 in solution. The assay of the solution is suitably fromabout 30% to about 50%, from about 35% to about 45%, or about 40%. Theyield of compound 320 is at least 50%, at least 60% or at least 70%.

The purification scheme for the solid ketone bisulfite adduct may alsobe used to purify compounds 120 and 321. In some particular aspects,compounds 130 and 160 may be prepared according to the methodhereinbefore described and depicted in FIG. 9 .

In some aspects of the invention, a sub-genus of compound 300,designated as compound 301 in the below reaction scheme, may be preparedfrom a trimethyl silyl intermediate of compound 320, designated ascompound 335 in the below reaction scheme. The reaction scheme is asfollows:

The method for preparing compound 301 comprises forming a first reactionmixture comprising a first polar aprotic solvent, methyl magnesiumchloride, copper (I) chloride, lithium chloride, chlorotrimethylsilane(TMSCl), and compound 330. Compound 301 is a sub-genus of compound 300where R^(1a) and R^(1b) are each independently selected from the groupconsisting of H and C₁₋₆ alkyl, R^(2b) is selected from the groupconsisting of H and C₁₋₆ alkyl, R^(3a) and R^(3b) are each H, and pis 1. In some aspects, R^(1a) and R^(1b) are each H and R^(2b) is —CH₃.In some aspects, compounds 330, 335 and 305 are of the species 110, 122and 130 respectively:

The first reaction mixture is reacted to form a first reaction productmixture comprising compound 335. The first reaction product mixture isquenched with a first quenching agent in aqueous solution and anon-polar water-immiscible solvent is added to the quenched reactionproduct mixture. Alternatively, the first reaction mixture is quenchedwith methanol as the first quenching agent, followed by a secondquenching agent in aqueous solution and a non-polar water-immisciblesolvent is added to the quenched reaction product mixture. The phasesare separated and an organic phase comprising the predominant amount ofcompound 335 is collected and concentrated to obtain compound 335 insolution. A second reaction mixture comprising a second polar aproticsolvent, phosphorous oxychloride, and the solution of compound 335 isformed. The second reaction mixture is reacted to form a second reactionproduct mixture comprising compound 301. The second reaction productmixture is quenched with a third quenching agent in aqueous solution.The phases are separated and an organic phase comprising the predominantamount of compound 301 in solution is collected.

The first and second polar aprotic solvents are as described elsewhereherein. In some aspects, the first polar aprotic solvent is THF. In someaspects, the second polar aprotic solvent is DMF. In some aspects, thefirst quenching agent is ammonium chloride. In some aspects, the firstquenching agent is methanol. In some aspects, the first quenching agentis methanol and the second quenching agent is ammonium chloride. In someaspects, the third quenching agent is potassium phosphate.

In some aspects, the first reaction mixture comprises from about 0.25 toabout 2 moles per liter of compound 330, or from about 0.5 to about 1.1moles per liter of compound 330. In some other aspects, the ratio of thevolume of the first polar aprotic solvent volume to compound 330 weightis about 3 L/kg, about 5 L/kg, about 5 L/kg, about 7 L/kg, about 9 L/kg,or about 11 L/kg, and ranges thereof, such as from about 3 to about 11L/kg, or from about 5 L/kg to about 9 L/kg. MeMgCl is present instoichiometric excess as compared to compound 330. In some aspects,MeMgCl is in solution in THF, such as a 3M solution. In some aspects,the mole ratio of MeMgCl to compound 330 is between 1:1 and 1.5:1, or isfrom about 1.1:1 to about 1.3:1. TMSCl is present in stoichiometricexcess as compared to compound 330. In some aspects, the mole ratio ofTMSCl to compound 330 is between 1:1 and 1.2:1, or from about 1.01:1 toabout 1.1:1. The mole ratio of CuCl to compound 330 is from about 0.05:1to about 0.2:1, or from about 0.05:1 to about 0.15:1. The mole ratio ofLiCl to compound 330 is from about 0.05:1 to about 0.2:1, or from about0.07:1 to about 0.15:1.

In some aspects, the second reaction product mixture comprises fromabout 0.5 to about 2 moles per liter or from about 0.7 to about 1.3moles per liter compound 335. The mole ratio of phosphorous oxychlorideto compound 335 is from about 1.5:1 to about 3.1:1, or from about 2.1:1to about 2.6:1.

In the first reaction, in some aspects, CuCl, LiCl, and the first polaraprotic solvent may be combined in an N₂ atmosphere in a reactor at atemperature of from about 10 to about 35° C. and cooled to from about−10 to about 10° C. Compound 330 and TMSCl are added to the reactor atfrom about −10 to about 10° C. MeMgCl is added to the reactor at fromabout −10 to about 10° C. A first reaction product mixture comprisingcompound 335 is formed. In some aspects, the reaction time to completionmay be at least 0.5 hours, at least 1 hour, at least 2 hours, at least4, or more. The reaction may be deemed complete when the area %concentration by HPLC of compound 330 is less than 5, less than 2, lessthan 1, less than 0.5, or less than 0.1. The reaction is quenched, suchas with an aqueous ammonium chloride solution wherein the equivalentratio of ammonium chloride to compound 330 is greater than 1:1, about1.1:1, about 1.2:1 or about 1.3:1. The ratio of ammonium chloridesolution volume to compound 330 is from about 2:1 to about 10:1 L/kg, orfrom about 3:1 to about 7:1 L/kg. Alternatively, the reaction is firstquenched with methanol, wherein the equivalent ratio of methanol tocompound 330 is about 0.25:1, about 0.5:1, or about 1:1. After the firstquench with methanol, the reaction is further quenched with an aqueousammonium chloride solution wherein the equivalent ratio of ammoniumchloride to compound 330 is greater than 1:1, about 1.1:1, about 1.2:1or about 1.3:1. The ratio of ammonium chloride solution volume tocompound 330 is from about 2:1 to about 10:1 L/kg, or from about 3:1 toabout 7:1 L/kg.

After the above quenching step(s), organic and aqueous phases areseparated and collected. The organic layer comprises compound 335 insolution and may optionally be washed with brine. The optionally washedorganic layer may be concentrated until the ratio of the distillatevolume collected to compound 330 weight is from about 8 L/kg to about 10L/kg. The concentrated first reaction product mixture may be dilutedwith a non-polar solvent (e.g., toluene) wherein the ratio of the addednon-polar solvent volume to compound 330 weight is from about 1 L/kg toabout 3 L/kg. In such aspects, the diluted mixture may concentrated toremove an approximate volume of the added non-polar solvent to produce asolution of compound 335. The compound 335 assay in the solution is fromabout 40 w/w % to about 60 w/w %, or from about 45 w/w % to about 55 w/w%. The yield of compound 335 based on compound 330 is at least 60%, atleast 70% or at least 80% and the HPLC purity of compound 335 is atleast 85 area % or at least 90 area % by HPLC.

In the second reaction, the solution from the first reaction is dilutedwith the non-polar solvent to achieve a compound 335 assay of from about25 to about 45 w/w % or from about 30 to about 40 w/w % or about 35 w/w%. In some aspects, the non-polar solvent is toluene. Water is added inan equivalent weight ratio of about 0.4:1 relative to compound 330.Water is added in an equivalent weight ratio of about 0.4:1 relative tocompound 330. A first POCl₃ addition may be done wherein the equivalentratio of POCl₃ to compound 330 weight is from about 0.2:1 to about 0.4:1or about 0.3:1 and wherein the temperature is from about 5 to about 35°C. DMF is added after POCl₃ at an equivalent ratio to compound 330 offrom about 1.5:1 to about 3:1 or from about 1.5:1 to about 2.5:1. Asecond POCl₃ addition is done wherein the equivalent ratio of POCl₃ tocompound 330 weight is from about 1.5:1 to about 2.5:1 or about 2:1, andthe mixture is heated to from about 50 to about 70° C. to form a secondreaction product mixture comprising compound 301. In some aspects, thereaction time to completion may be at least 2 hours, at least 4 hours,at least 8 hours, at least 12 hours, or more. The reaction may be deemedcomplete when the area % concentration by HPLC of compound 330 is lessthan 5, less than 2, less than 1, less than 0.5, or less than 0.1. Thereaction product mixture is combined with an aqueous potassium phosphatesolution providing an equivalent ratio of potassium phosphate tocompound 330 is from about 1.2:1 to about 2:1 or from about 1.4:1 toabout 1.8:1. The ratio of potassium phosphate solution volume tocompound 330 weight is from about 3 to about 12 L/kg or from about 6 toabout 9 L/kg. Organic and aqueous phases are formed that are separatedand collected. The organic layer is washed with potassium phosphatesolution and water to obtain a washed organic phase (e.g., toluene)comprising compound 301 in solution and having a pH in excess of 7. Theorganic phase is filtered to generated compound 301 in solution (e.g.,toluene). The yield of compound 301 based on compound 330 is at least70% or at least 75%, and the purity of compound 301 is at least 85% orat least 88% by HPLC.

The purification scheme for the trimethylsilyl intermediate may be usedto purify compounds 120 and 321. In some particular aspects, compounds130 and 160 may be prepared according to the method herein beforedescribed and depicted in FIG. 10 .

Also provided herein is a method of preparing compound 200,stereoisomers thereof, geometric isomers thereof, tautomers thereof, andsalts thereof,

the method comprising:

-   -   (i) (1) forming a first reaction mixture comprising compound        170, a reducing agent, a base and a solvent, to reduce the        aldehyde moiety of compound 170 to form compound 171, and        -   (2) isolating compound 171 from the first product mixture,    -   (ii) (1) forming a second reaction mixture comprising compound        171, compound 182, a palladium catalyst, a solvent system        comprising water, and a base, to form compound 200, and        -   (2) isolating compound 200 from the second product mixture,            according to the following scheme:

In some aspects, the reducing agent in step (i) is NaBH₄. In someaspects, the base in step (i) is K₂HPO₄. In some aspects, the solvent instep (i) is THF. In some aspects, the Pd catalyst in step (ii) isPd(PCy₃)₂. In some aspects, the base in step (ii) is K₃PO₄, Et₃N orDi-isopropylethylamine. In some aspects, the equivalent ratio of the Pdcatalyst to compound 171 is less than 0.05:1. In some aspects, the ratioof compound 182 to compound 171 is greater than 1:1.

Also provided herein is a compound having the structure:

wherein X is selected from the group consisting of Cl, Br, and I. Insome embodiments, X is Cl. In some embodiments, X is Br.

EXAMPLES

The Figures and Examples provide exemplary methods for preparing thedisclosed compounds; those skilled in the art will appreciate that othersynthetic routes may be used to synthesize the compounds. Althoughspecific starting materials and reagents are depicted and discussed inthe Figures and Examples, other starting materials and reagents may besubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the described and exemplary methods maybe further modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

In the Examples, equivalents and equivalent ratios are based on thereferenced starting material for each reaction. Volume per weightvalues, such as L/kg and mL/g, refer to a volume of a liquid componentbased on the weight of the referenced starting material for eachreaction.

Analytical Methods

High pressure liquid chromatography (HPLC) may be performed as follows.

Examples 1, 2, 10B and 10E (final compound). HPLC Column: Waters XSelectCHS C18 (150 mm*3.0 mm*3.5 μm). Mobile Phase A: 10 mM ammonium formatepH 3.7. Mobile Phase B: CH₃CN. Flow Rate: 1.0 mL/min. Injection Volume:5.0 uL to 10.0 uL. Column Temperature: 45° C. UV Detection Wavelength:245 nm. Diluent: 30:70 (v/v) CH₃CN/H₂O.

Examples 5 to 8. Column: Waters Atlantis T3 (4.6*150 mm 3 μm). MobilePhase A: 10 mM ammonium formate pH 3.7. Mobile Phase B: CH₃CN. FlowRate: 1.0 mL/min. Injection Volume: 2.0 uL. Column Temperature: 45° C.UV Detection Wavelength: 315 nm. Diluent: CAN.

Example 10C. Column: (1) Agilent PLRP-S 100 A, 150 mm×4.6 mm, 3 μm or(2) Agilent PLRP-S 100 A, 250 mm×4.6 mm, 5 μm. Mobile phase A: 10 mMaqueous NaOH. Mobile phase B: acetonitrile. Flow Rate: 1.0 mL/min.Injection Volume: 1.0 uL. Column temperature: (1) 20° C.; (2) 15° C.

Example 1 (10D in-process test), example 10E (compound 190 in processtest) and borane adduct in process test. Column: ACE Excel C18 HL (50×3mm, 3 μm). Mobile Phase A: Water with 0.05% TFA. Mobile Phase B: CH₃CNwith 0.05% TFA. Flow Rate: 1.0 mL/min. Injection Volume: 2.0 uL. ColumnTemperature: 35° C. UV Detection Wavelength: 220 nm. Diluent: Methanol.

Example 10D final compound 190. Column: Agilent Poroshell EC-C18 (150×3mm, 2.7 μm). Mobile Phase A: 10 mM ammonium formate in water. MobilePhase B: CH₃CN. Flow Rate: 0.5 mL/min. Injection Volume: 5.0 uL. ColumnTemperature: 30° C. UV Detection Wavelength: 245 nm.

Liquid chromatograph mass spectrometry (LCMS) may be performed asfollows. Column: XDB-C18 4.6 mm×50 mm, 1.8 μm. Mobile Phase A:Water/0.05% TFA. Mobile Phase B: CH3CN/0.05% TFA. Flow Rate: 1.2 mL/min.Injection Volume: 10.0 uL. Column Temperature: 40° C. Diluent: 30:70(v/v) CH₃CN/H₂O. Interface Type: ES-API+. Drying Gas Temp: 250° C.Nebulizer Pressure: 35 psig. Drying Gas Flow: 13 L/min. CapillaryVoltage: 3000 V. Scan Range: 150-600 m/z.

Gas chromatography (GC) may be performed as follows. An Agilent 7890 Aseries GC system with an Agilent HP-5 (30 m*0.32 mm*0.25 μm) column.Flow rate: 2.0 mL/min. Injection volume: 10.0 uL. Carrier gas: N₂.Diluent: methanol.

Mass spectrometry (MS) may be performed using a (1) Sciex 15 massspectrometer in ES+ mode, or (2) Shimadzu LCMS 2020 mass spectrometer inESI+ mode. Mass spectra data generally only indicates the parent ionsunless otherwise stated. MS or HRMS data is provided for a particularintermediate or compound where indicated.

Nuclear magnetic resonance spectroscopy (NMR) may be performed using anysuitable instrument, including, but not limited to, a (1) Bruker AV III300 NMR spectrometer, (2) Bruker AV III 400 NMR spectrometer, or (3)Bruker AV III 500 NMR spectrometer, and referenced to tetramethylsilane.NMR data is provided for a particular intermediate or compound whereindicated.

Example 1

7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one(Compound 160) was prepared according to the reaction scheme in FIG. 8 .

In a first step, compound 120 was prepared from compound 110 as follows:

Three batches of compound 120 were separately prepared, with each batchbased on 53.3 kg (554.6 mol, 1.0 equiv) of compound 110(3-methylcyclopent-2-en-1-one) starting material.

For each batch, a dry 1000 L jacket reactor equipped with an agitator, atemperature probe and a nitrogen inlet, was charged THF (458.6 kg) undera N₂ atmosphere. CuCl (11.2 kg, 113.1 mol, 0.2 equiv), was charged tothe reactor over 10 minutes with stirring. The reactor was cooled to−20±5° C. and MeMgCl in THF (3M, 18.7 kg, 0.1 equiv) was added to thereactor while maintaining the temperature at −20±5° C. The mixture wasstirred for 15 minutes followed by addition of 3-methylcyclopent-2-enone(53.3 kg, 554.6 mol, 1.0 equiv) to the reaction mixture whilemaintaining the temperature at −20±5° C. The remaining MeMgCl (3M, 203.2kg, 1.1 equiv) was charged, again maintaining the temperature at −20±5°C. The addition was complete in 2.5 hours. The reaction mixture wasstirred at −20±5° C. for 2 hours. The reaction completion was confirmedby GC with the starting material concentration of less than 4%.

Compound 120 (3,3-dimethylcyclopentan-1-one) was isolated from thereaction product mixture as follows. Aqueous HCl solution (6% w/w, 485.3kg) was added to the reaction product mixture slowly over 1.5 h toadjust the pH to 3 to 4. The mixture was stirred for a further 30minutes. The THF phase was separated and transferred to another vessel.The aqueous phase was extracted with MTBE (202.7 kg). The MTBE phaseseparated and combined with the THF phase. The combined organic layerwas washed with aqueous NaHCO₃ (26.7 kg, water 293.3 kg), followed bybrine (NaCl 117.3 kg, water 522.6 kg). The organic layer was dried overNa₂SO₄ (144.0 kg) for 4 hours, followed by removal of the Na₂SO₄ bycentrifugation. The solution was concentrated (at 1 atm) between 50 and70° C. to a final concentration of 55 to 65 L.

The concentrated solution of each batch were combined and transferred to20 L reaction flask equipped with a condenser for distillation. By a3-stage fractional distillation: (1) solvents were removed first (frontfraction); (2) compound 120 was removed second in a major distillationfraction (internal temperature of less than 110° C.); and (3) a lastdistillation fraction. A residue remained after removal of the lastdistillation fraction. The major distillation fraction, collectedbetween 60-90° C. (P≤−0.09 MPa), afforded product compound 120 as acolorless oil. The isolated product contained 81.5 kg of compound 120,with a 43.6% isolated yield, and 98.6% purity by HPLC. The compound 120assay yield of the front fraction was 0.2%, the compound 120 assay yieldof the last distillation fraction was 2.0%, and the residue contained0.9% compound 120. The major component identified in the residue was ofthe structure wherein the concentration was 11.5 A % by HPLC:

In a second step, compound 130 was prepared from compound 120 in fourseparate batches as follows:

For each batch, a 500 L reactor was charged with DCM (287.3 kg, 8 L/kg)and N,N-dimethylformamide (44.0 kg, 602.1 mol, 2.5 equiv) under a N₂atmosphere. The reaction mixture was cooled to 13±5° C. and POCl₃ (77.5kg, 505.4 mol, 2.10 equiv) was added dropwise maintaining thetemperature at 13±5° C. After addition was complete, the mixture wasstirred for 1 hour at 13±5° C. Compound 120(3,3-Dimethylcyclopentan-1-one) (27.0 kg, 240.6 mol) was charged to thereaction mixture dropwise maintaining the temperature at 13±5° C. Afteraddition was complete, the mixture was stirred for 1 hour at 20±5° C.The reaction was then heated to 45±5° C. and stirred for 18-24 hours.The reaction completion was confirmed by GC with compound 120concentration of less than 5%. The reaction mixture was cooled to 25±5°C.

For each batch, a solution of compound 130(2-chloro-4,4-dimethylcyclopent-1-ene-1-carbaldehyde) was generated fromthe reaction product mixture as follows. A 1000 L reactor was chargedwith water (270.0 kg, 10 L/kg) and heated to 40±5° C. The reactionproduct mixture was added dropwise while maintaining the temperature at40±5° C. Once addition was complete, the mixture was stirred for 30minutes at 40±5° C. The reaction mixture was cooled to 25±5° C., andfiltered through a pad of Celite®. The organic phase was separated andwashed with water (108.0 L×2). The organic phase was then washed withbrine (108.0 L), and the organic layer was concentrated to a totalvolume of 3 L/kg under vacuum below 40° C. NMP (27.8 kg, 1 L/kg) wascharged and the mixture, and the mixture was concentrated to 54 L undervacuum below 40° C. The residue was cooled to 25±5° C. to afford crudecompound 130 in NMP.

In a third step, compound 160 was prepared from compounds 130 and 10 asfollows in four separate batches as follows:

For each batch, a 300 L reactor was charged with NMP (83.2 kg, 3 L/kg),4-methylmorpholine (29.2 kg, 288.8 mol, 1.2 equiv) and compound 10(piperazin-2-one) (21.1 kg, 211.8 mol, 0.88 equiv) under a N₂atmosphere. The reaction mixture was heated to 115±5° C. The solution ofcrude compound 130 in NMP was added dropwise maintaining the temperatureat 115±5° C. The reaction mixture was stirred for 30 minutes at 110±5°C. The reaction completion was confirmed by GC with compound 160concentration of no more than 5%.

For each batch, solid compound 160(7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one)was obtained as follows. The reaction product mixture was cooled to90±5° C., and water (135.0 kg, 5 L/kg) was then charged. The mixture wasthen further cooled to 60±5° C. To a separate 500 L reactor was chargedwater (135.0 kg, 5 L/kg), followed by addition of the reaction productmixture. The mixture was cooled to 25±5° C. and stirred for at least 3hours at 25±5° C. Solid compound 160 was collected by centrifugefiltration. The collected solids were slurried in acetone (64.8 kg, 3L/kg) for at least 3 hours at 25±5° C. The solid was collected bycentrifuge filtration to afford wet crude compound 160 (30.1 kg).

The four batches of solid crude compound 160 were combined and slurriedin heptane, isolated, and dried. The structure of compound 160 wasidentified by LCMS and as having a molecular weight of 206.32. The totalcompound 160 yield for steps 2 and 3 was 75.8 kg, the isolated yield forsteps 2 and 3 was 51.1% and the purity was 98.5 A % by HPLC. The primaryimpurity was identified by LCMS as the dimer below having a molecularweight of 420.55 with a concentration of 1 Area %:

Example 2

Compound 160 was prepared according to the reaction scheme in FIG. 9 .

In a first step, compound 120 was prepared from compound 110 as follows:

THF (1352 L, 8 volumes) was charged to a reactor under nitrogen andstart stirring. Copper(I) chloride (35.49 kg, 0.2 eq) was charged to thereactor and the contents were cooled to −20±5° C. 59.15 kg of methylmagnesium chloride (22% in THF, 3 molar) (0.1 eq) was charged drop-wiseto the reaction mixture while maintaining the temperature at −20±5° C.The contents of the reactor were stirred for 15 min at −20±5° C. 169.5kg (1.0 eq) of Compound 110 (3-methylcyclopent-2-en-1-one) was chargedto the reactor at −20±5° C. and the contents were stirred for 15 min at−20±5° C. 657.41 kg methylmagnesium chloride (22% in THF, 3M) (1.1 eq)was added dropwise at −20±5° C. to the reactor and the contents werestirred at −20±5° C. for at least 2 h. The reactor contents were sampledevery 1 h and analyzed by GC until the concentration of compound 110 wasno more than 4%.

The reaction product mixture was combined with 676 L HCl aqueoussolution (4V, 1.3 eq HCl) while maintaining the temperature at 5±5° C.,and the contents were stirred for an additional 30 min. To the reactorwere then charged 2197 L hexane (13V) and 243 Kg NaCl, and the mixturewas warmed to 20±5° C. and stirred for 1 h. 101 kg Celite was charged tothe reactor and stirred for 30 min. The mixture was centrifuged and thecollected solid compound 120 was washed with 169 L hexane. The filtratewas held for at least 30 minutes and separated. The organic phase wasconcentrated to about 338 L (2V) at a temperature below 75° C. and atnormal pressure. The concentrated organic phase was cooled to 20±5° C.and filtered for form concentrated crude compound 120.

In a separate reactor, 845 L water (5V) was combined with 690 Kg NaHSO₃(3.77 eq) with stirring. The concentrated crude compound 120 was chargedto the reactor at 25±5° C. and the contents were stirred for 18 h at25±5° C. Solid compound 121 was collected by centrifugation and wasslurried in 1183 L hexane (7V) for at least 10 h at 25±5° C. The mixturewas centrifuged and the collected solid compound 121 was washed with 338L DCM (2V).

In a separate reactor, 1690 L water (10V) was combined with the solidcompound 121 and stirred for 30 minutes. 845 L DCM (5V) was charged tothe reactor. 221.8 Kg NaHCO₃ (1.5 eq) was charged to the reactor inportions at 25±5° C. and the contents were stirred for 18 h at 25±5° C.to form compound 120 in solution. 20 kg Celite was charged to thereactor with mixing and the reactor contents were centrifuged. Thecentrifugate was held for at least 3 h and a formed emulsion. Theemulsion was separated to form an organic phase and an aqueous phase.The aqueous phase was extracted with 169 L DCM (1V) and the organicphases were combined. The combined organic phases were further combinedwith 338 L brine (2V), and an emulsion occurred. The emulsion wasstirred for at least 30 mins and allow to sit for at least 3 h toseparate into phases. The phases were separated. The organic phase wasconcentrated to about 2V at no more than 70° C. under normal pressure toyield 313.5 kg DCM solution comprising compound 120. The concentratedorganic phase was cooled to 20±5° C. The concentrated solution contained41.1% compound 120 as analyzed by GC for a total yield of 64.6%. Thecompound 120 purity was from 99.2 to 99.7 area % by HPLC.

In a second step, compound 130 was prepared from compound 120 asfollows:

A reactor was prepared by reducing the pressure to ≤0.08 MPa and thenpurging with nitrogen to atmosphere. The preparation was repeated threetimes. The reactor was charged with 399 kg of DCM (4.0V) and 163 kg ofDMF (2.5 eq) with stirring and cooling to 13±5° C. The reactor wascharged with 287 kg of POCl₃ (2.1 eq) dropwise at 13±5° C. and stirredfor 1 h at temperature. The reactor was then charged with 100 kg ofcompound 120 solution (1.0 eq) dropwise at 13±5° C. and stirred at 20±5°C. for 1 h followed by heating to 42±3° C. After 20 hours at 42±3° C.the content of compound 120 in the reaction product mixture asdetermined by GC was no more than 2.0%. The reaction product mixture wascooled to below 30° C. The reactor was charged with 285 kg of DMF (3.0V)and stirred for 10 min.

A separate reactor was charged with 1000 kg of purified water (10V) andheated to 40±3° C. The admixture of the reaction product mixture and DMFwere charged dropwise to the reactor containing the water at 40±3° C.and the contents were stirred for at least 30 min after quenching thesolution. The quenched reaction product mixture was cooled to 25±5° C.,charged with 40 kg of Celite (0.4 w/w), further charged with 399 kg ofDCM (3.0V), and stirred for at least 30 min. The mixture was centrifugedand the collected solids were washed with 133 kg DCM (1.0V). Thecentrifugate was stirred for at least 30 min and allowed to settle forat least 30 min. The phases were separated and the organic phase wascollected. The aqueous phase was extracted with 532 kg DCM (4.0V), theDCM extract was combined with the collected organic phase, and thecombined organic phases were washed with 400 kg H₂O (4.0V). The phaseswere separated and the organic phase was washed with 400 kg H₂O (4.0V).The washed organic phase was further washed with 400 L brine (4.0V). Thephases were separated and the organic phase was concentrated to 3±0.5V.130 kg of petroleum ether (2.0V) was added to the concentrated organicphase that was then concentrated to 3±0.5V. This was repeated two moretimes. The concentrated organic phase was charged with 103 kg of NMP(1.0V) that was then concentrated to 2.5±0.5V to yield a solution ofcompound 130.

In a third step, compound 160 was prepared from compound 130 as follows:

A reactor was prepared by reducing the pressure to ≤0.08 MPa and thenpurging with nitrogen to atmosphere. The preparation was repeated threetimes. The reactor was charged with 309 kg of NMP (3.0V) and 108 kg ofN-methylmorpholine (1.2 eq) with stirring. The reactor was then chargedwith 79 kg of piprazin-2-one (0.88 eq) and heated to 105±5° C. Thesolution of compound 130 from the second step was charged to the reactorat 105±5° C. After 30 minutes of reaction at 105±5° C., the content ofcompound 130 in the reaction product mixture was no more than 5% by GC.The reaction product mixture was cooled to about 90±5° C. and 1000 kg ofwater (10V) was charged to the reactor. The reactor contents were cooledto 15±5° C. and were stirred for at least 3 h at 15±5° C. The reactorcontents were centrifuged and the collected solids were slurried in 1000kg water (10V) for at least 3 h at 20±5° C. The slurry was centrifugedand the collected solids were slurried with 240 kg acetone (3V) for atleast 3 h at 25±5° C. The slurry was centrifuged and the collectedsolids were washed with 80 kg acetone (1V). The washed solids were driedin a vacuum oven at 35±5° C.

The isolated yield for steps 2 and 3 was 57.3% and the purity for steps2 and 3 was 99.9 area % by HPLC.

As compared to Example A, it is believed that removal of DCM by solventswitch reduced formation of the dimer impurity.

Formation of the ketone bisulfide adduct of compound 121 allowed forisolation of the adduct as a solid by filtration thereby leaving darkimpurities in the mother liquor and provide for a purity of compound 120on the order of 99% as measured by GC. Furthermore, the yield in thestep for forming compound 120 was increased to 64.6%.

Example 3

Compound 160 was prepared according to the reaction scheme in FIG. 10 .

In a first step, compound 122 was prepared from compound 110 as follows:

Copper (I) chloride (2.58 g, 0.05 eq) and lithium chloride (2.21 g, 0.1eq) were dissolved in THF (325 mL, 6.5 relative volume) in a reactionreactor under an inert atmosphere at a temperature of 15-30° C. followedby cooling to −5 to 5° C. Compound 110 (50.0 g, 1.0 eq) andchloromethylsilane (59.33 g, 1.05 eq) were added to the reactor via anaddition funnel at −5 to 10° C. Methylmagnesiumchloride (210.76 g, 1.2eq.) was added to the reactor via an addition funnel at −5 to 10° C.followed by a funnel rinse with THF (25 mL, 0.5 rel. vol.) to thereactor. A suspension formed that was stirred for 0.5 to 1 h at −5 to10° C. The concentration of compound 110 was no more than 2.0 area % byHPLC.

The suspension was warmed to 15 to 20° C. and stirred for 15 to 30minutes. Subsequently, methanol (4.16 g, 0.25 eq.) was added at 15 to20° C. within at least 20 minues and stirred for at least another 15minutes The suspension was transferred to a quench reactor and wasquenched at 10 to 40° C. onto 12 w/w % ammonium chloride solution (250mL, 5 rel. vol., 1.1 eq). The reaction reactor was rinsed with toluene(100 mL, 2.0 rel. vol.) into the quench reactor to form an emulsion thatwas stirred for 30 minutes followed by temperature adjustment to 20 to30° C.

The phases were separated to obtain organic layer 1 (612.2 g, 695 mL)and aqueous layer 1 (325.1 g, 275 mL). Organic layer 1 was washed with20 w/w % brine (100 mL, 2 rel. vol.) and the phases were separated toform organic layer 2 (608.6 g, 690 mL) and aqueous layer 2 (114.1 g, 102mL). Organic layer 2 was concentrated at 65 to 90° C. and 800 to 300mbar to about 500 mL distillate (10 rel. vol.). The residue was dilutedwith toluene (100 mL, 2.0 rel. vol.) and concentrated at 65 to 90° C.and 700 to 200 mbar until about 100 mL distillate (2 rel. vol.) iscollected. Compound 122 is present in solution in toluene. The solutionassay was 53 w/w % compound 122, the yield of compound 122 was 80%, andthe purity of compound 122 by HPLC was 89 area %.

In a second step, compound 130 is prepared from compound 122 as follows:

The solution of compound 122 (115.4 g, 136 mL, 2.7 rel. vol., 1 eq.) wascharged to a reactor under an inert gas atmosphere and was diluted withtoluene (27.5 g, 0.6 rel. vol.) to an adjusted compound 122 assay of 35w/w %. Water (1.95 g, 0.4 eq.) was added to the reactor followed byphosphorous oxychloride (13.7 g, 0.33 eq.) at a temperature of 10 to 30°C. An emulsion formed that was stirred at temperature for at least 30minutes upon which water droplets were not detectable. DMF (39.7 g, 2.0eq.) was added at 10 to 30° C. followed by addition of phosphorousoxychloride (87.3 g, 2.1 eq.) at 10 to 60° C. followed by heating to 55to 65° C. for 6 to 8 h. An emulsion formed that was cooled to 30 to 40°C. The emulsion was transferred to a quench reactor and was quenched at20 to 45° C. onto 20 w/w % potassium phosphate solution (375 mL, 453.8g, 7.5 rel. vol., 1.6 eq.). The reactor was rinsed with toluene (10 mL,0.2 rel. vol.) to the quench reactor and the emulsion was stirred for30-60 min and adjusted to 20 to 30° C.

The phases were separated to obtain organic layer 1 (144.3 g, 162 mL)and aqueous layer 1 (575.6 g, 473 mL). Organic layer 1 was washed with amixture of 20 w/w % potassium phosphate solution (50 mL, 60.5 g, 1.0rel. vol., 0.2 eq.) and water (50 mL, 1.0 rel. vol.). The organic layerwas filtered to obtain compound 130 in solution in toluene (155 mL, 3.1rel. vol.), the solution having a compound 130 purity of 58 area % byHPLC.

In a third step, compound 160 is prepared from compound 130 as follows:

In a reactor, N-ethyldiisopropylamine (42.2 g, 1.2 eq) andpiperazin-2-one (compound 10) (21.7 g, 0.8 eq.) are suspended in DMF(150 mL, 3.0 rel. vol.) under an inert gas atmosphere followed byheating to 110 to 115° C. Compound 130 in toluene from step 2 (155 mL,3.1 rel. vol.) were added at 110 to 115° C. and stirred for 90-120 minat temperature. A reaction product mixture solution resulted that wascooled to 60 to 90° C. Unreacted compound 130 was no more than 1 area %by HPLC. Water (50 mL, 1.0 rel. vol.) was added to the reaction productmixture at 85 to 95° C. followed by cooling to 75 to 85° C. to form asuspension of compound 160. The suspension was cooled to 20 to 30° C.,water (200 mL, 4.0 rel. vol.) was added, and the suspension was stirredfor at least 1 h. The suspension was filtered to yield wet crudecompound 160 (DMF/toluene/water). Crude compound 160 was slurried inacetone (150 mL, 3.0 rel. vol.) at 20 to 30° C. for at least 30 minutes.Wet compound 160 was collected and was washed with acetone (2×50 mL,2×1.0 rel. vol.) to yield purified wet compound 160 (26 g) that was thendried at 70° C. and ≤50 mbar.

The yield of compound 160 was: 42% of theoretical based on step 1(compound 122); 53% of theoretical based on piperazin-2-one; and 34% oftheoretical based on compound 110 (3-methylcyclopent-2-en-1-one). Thepurity of compound 160 was 99.8 area % by HPLC and the assay of compound160 was 98.0 area % by HPLC.

Example 4

Compound 90 was prepared according to the reaction scheme in FIGS. 3 and4 .

In a first step, compound 70 was prepared from compound 60 as follows;

Compound 60 (425.0 kg, 1 eq.) and CH₃CN (4713 kg) were charged to areactor with agitation and the temperature was adjusted to from 5 to 20°C. N-bromosuccinimide (1631.0 kg, 2.05 eq.) was charged to the reactorwith agitation over a period of 30 hours while maintaining thetemperature below 20° C. The temperature was adjusted to 5 to 15° C. andagitated a temperature for 4 hours. The reaction product mixture wassampled and compound 60 was not detectably by HPLC. The mixture wascooled to −5 to 5° C. over 3 hours and was agitated for 6 hours attemperature. Na₂S₂O₃·5 H₂O (77 kg in solution in 425 kg water) wascharged to the mixture in 90 minutes while maintaining the temperatureat −5 to 5° C. The mixture was filtered and compound 70 was isolated asa wet cake by filtration. The wet cake was rinsed with CH₃CN (850 kg).The solid compound 70 and water (6800 kg) was charged to a reactor andthe mixture was agitated at 45 to 55° C. for 2 hours. The mixture wasfiltered to isolate compound 70. The solid compound 70 and water (6800kg) was charged to a reactor and the mixture was agitated at 45 to 55°C. for 2 hours. The mixture was filtered and 912 kg compound 70(3,5-dibromopyridin-2(1H)-one) was obtained at a yield of 81%. Thepurity was 99.2 area % by HPLC and 99.9% weight assay by HPLC.

In a second step, compound 90 was prepared from compound 70 as follows:

Compound 70 (752 kg, 99.9% assay by HPLC, 1 eq.) and dimethylformamidewere charged to a reactor. K₂CO₃ (728 kg, 1.77 eq.) and water (5654 kg)were charged to the reactor with agitation at 20 to 30° C., and themixture was cooled to 5 to 10° C. PTSM (843 kg, 1.52 eq.) was addeddropwise while maintaining the temperature at 10 to 15° C. The mixturewas agitated for 20 hours at 15 to 25° C. The reaction product mixturewas sampled and 1% of compound 70 was detectably by HPLC. The reactionmixture was cooled to 0 to 5° C. and agitated at temperature for 3hours. The mixture was filtered and compound 90(3,5-dibromo-1-methylpyridin-2(1H)-one) was isolated as a wet cake thatwas then washed with water (2923 L). Anhydrous ethanol (4496 L) wascharged to a reactor and combined with compound 90 wet cake withagitation. The mixture was agitated at 20 to 25° C. for 3 hours,followed by cooling to 0 to 5° C. and agitation for 3 hours. The mixturewas filtered to isolate compound 90 that was dried under reducedpressure at a temperature of less than 40° C. for 20 hours to yield679.3 kg compound 90. The conversion of compound 70 to compound 90 was99% with a purity of 93 area % including 2.8% byproduct.

Example 5

Compound 154 was prepared according to the reaction scheme in FIGS. 3and 4 .

In a first step, compound 40 was prepared from compound 30 as follows:

Water (500 g, 5 w/w %) was charged to a reaction flask. Compound 30(2-methylpiperazine) (100 g, 998.4 mmol, 1 eq.) was charged to thereaction flask with agitation. HCl (36% aqueous, 102.1 g, 1008 mmol,1.01 eq.) and methanol (200 g) were charged to the reaction flask withagitation. A solution of Boc₂O (222 g, 1008 mmol, 1.01 eq.) in methanol(200 g) was added dropwise to the reaction flask at 15 to 25° C.followed by stirring for 18 hours at 20 to 30° C. The flask contentswere evaporated to dryness in vacuo at 40 to 50° C. to form a residue.Water (500 g) was added to the residue and the mixture was stirred for 1hours. The mixture was filtered and the collected solids were washedwith water (50 g). The aqueous filtrate was extracted with ethylacetate(500 mL). The extracted aqueous phase was adjusted to a pH in excess of12 with 30% NaOH and was then extracted with ethylacetate (500 mL) threetimes. The organic phase was washed with brine (500 g) twice and wasthen dried with anhydrous Na₂SO₄. The dried mixture was filtered and thecollected solids were rinsed with ethylacetate (100 mL). The filtratewas concentrated to dryness in vacuo at 50 to 60° C. and furtherconcentrated under high vacuum (5 mm Hg) at 65 to 75° C. for 3 hours toyield compound 40 (tert-butyl 3-methylpiperazine-1-carboxylate). Thepurity of compound 40 was 97.7 area %, the assay was 95.9% and the yieldwas 76.4%.

Compound 40 was prepared under various conditions of temperature,catalyst loading, strict air-free conditions and exposure to a traceamount of air according to the above method. The results are reported inExample 5 Table 1 below where “Exp.” refers to experiment and “Cmpd.”refers to compound.

TABLE 1 Example 5 Conditions Purity Cmpd. Cmpd. T Cmpd. Cmpd. Exp Air 5040 Pd(OAc)₂ BINAP (° C.) 50 154 1 trace   5 mmol   5 mmol 0.02 eq. 0.02eq. 70-75 65.8 A % 25.1 A % 2 trace  20 mmol  20 mmol 0.01 eq. 0.01 eq.90-95 31.3 A % 63.2 A % 3 trace  10 mmol  10 mmol 0.02 eq. 0.02 eq.90-95 0.48 A % 93.1 A % 4 none 6.3 mmol 6.3 mmol 0.01 eq. 0.01 eq. 90-95 1.3 A %   94 A %

In a second step, compound 154 was prepared from compounds 40 and 50 asfollows:

Dioxane (1.5 L, 10 v/w %) was charged to a reaction flask and agitationwas started. The reaction flask was evacuated and refilled with N₂ threetimes. Compound 50 (118.7 g, 733.7 mmol, 1.02 eq.), compound 40 (150 g,718 mmol, 1.0 eq.), and K₃PO₄ (318 g, 1468 mmol, 2.09 eq.) were chargedto the reaction flask with constant flow of N₂. The reaction flask wasevacuated and refilled with N₂ three times. Pd(OAc)₂ (3.4 g, 15.1 mmol,0.021 eq.) catalyst and BINAP ligand (9.3 g, 14.9 mmol, 0.021 eq) wereadded to the reaction flask with constant flow of N₂. The reaction flaskwas evacuated and refilled with N₂ three times and N₂ flow was continuedfor 1 h. The mixture was heated to 95 to 105° C. and stirred attemperature for 15 h under N₂ flow. The reacted mixture was cooled to 50to 60° C. and filtered at that temperature. The collected solids werewashed with hot dioxane. The liquid filtrate was concentrated to drynessin vacuo at 50 to 60° C. to form a residue. i-propanol (300 g) wascombined with the residue and the mixture was slurried at −5 to 5° C.for 1 hour and then filtered. The collected solids were washed with coldi-propanol. The wet solids were dried in vacuo at 60 to 70° C. to yieldcompound 154 (t-butyl(S)-3-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate). Thepurity of compound 154 was 99.5 area % by HPLC, the assay was 94.4% andthe yield was 80.5%.

Compound 153 was produced in a second method wherein the halogen ofcompound 50 was bromine according to the following reaction scheme:

Compound 30 (299.98 g) was charged to a reactor followed by water (1.5L) under a N₂ blanket. The mixture was stirred at 20 to 30° C. untilclear. 37% HCl (299.41 g) was charged to the reactor over a period ofabout 1 hour under a N₂ blanket to a final pH of about 7.1. The mixturewas stirred at 20 to 30° C. for 30 minutes. (Boc)₂O (654.05 g in 1.5 Lmethanol) was added to the reactor under a N₂ blanket over a period ofabout 2.5 hours. The mixture was stirred at 20 to 30° C. for 18 hours.The mixture was sampled and tested by HPLC indicating 6.2 area %compound 30 and 90.4% compound 40. (Boc)₂O (26.2 g) was added to thereactor and the mixture was stirred at 20 to 30° C. for 2.5 hours. Themixture was sampled and tested by HPLC indicating 3.2 area % compound 30and 92.8% compound 40. The reactor jacket temperature was adjusted to 40to 45° C. and the mixture was concentrated to remove methanol to a finalmethanol concentration of 0.06%.

Water (1200 mL) was charged to the mixture in the reactor followed byethyl acetate (600 mL), and the resulting mixture was stirred at 20 to25° C. for 1 hour. Agitation was stopped and the mixture was allowed tosettle and separate to an ethyl acetate layer and an aqueous layer.Ethyl acetate (600 mL) was added to the aqueous layer, and the resultingmixture was stirred at 20 to 25° C. for 30 minutes. Agitation wasstopped and the mixture was allowed to settle and separate to an ethylacetate layer and an aqueous layer. 30% NaOH solution (900 g) was addedto the aqueous layer to adjust the pH to about 11. The pH 11 aqueouslayer was extracted with ethyl acetate (600 mL) three times. Residualcompound 40 in the aqueous layer was 0.02% and compound 40 loss was0.12%. The ethyl acetate layers were combined and the combined layerswere washed with 5% aqueous Na₂SO₄ (900 mL) two times. Compound 40residual in the Na₂SO₄ layer was 0.83% and compound 40 loss was 2.9%.The ethyl acetate phase was concentrated to 900 mL under reducedpressure at 40 to 50° C. 1,4-dioxane (900 mL) was added and to theconcentrate mixture, and the volume reduced to 900 mL under reducedpressure at 40 to 50° C. A solution of compound 40 in dioxane (923.63 g)was obtained having a residual ethyl acetate content of 0.31% and awater content by KF of 2.31%. A portion of the compound A/dioxanesolution (30.8 g) was concentrated to dryness under high vacuum at 40 to50° C. Compound A (16.44 g) was obtained and the compound 40 purity was93.1% by qNMR and the compound 40 yield was 76.6%.

Compound 40 (200 g, 998 mmol) and compound 51 (206.76 g, 1019 mmol) werecharged to a reactor followed by dioxane (1000 mL, 5 vol.). K₃PO₄ (436.7g) was charged in portions to the reactor at 20 to 30° C. The reactorcontents were stirred at 20 to 30° C. for 1 hour while sparging with N₂.Pd(OAc)₂ catalyst (4.65 g) and BINAP ligand (12.84 g) were added to thereactor under a N₂ blanket, the temperature was adjusted to 20 to 30° C.and the mixture in the reactor was stirred at that temperature of 16hours under a N₂ blanket to form compound 154. The temperature wasadjusted to 55 to 65° C. and water (600 mL) was added to the reactorover 15 minutes and the mixture was stirred for 20 minutes at 55 to 65°C. The phases were separated and collected and the aqueous phase wasextracted with dioxane (400 mL) at 55 to 65° C. The organic layers werecombined and the temperature was adjusted to 20 to 30° C. Compound 154seed crystals (0.894 g) added to the combined organic layers and themixture was stirred at 20 to 30° C. for 30 minutes. Water (1200 mL) wasslowly added to the mixture followed by stirring at 20 to 30° C. for 10hours to produce compound 154 crystals. Thereafter, the temperature wasreduced to 0 to 10° C. and the mixture was stirred at that temperaturefor 1.5 hours. The mixture was filtered to collect compound 154 crystalsthat were then washed with 0 to 10° C. water (400 mL) to produce 741.8 gwet solid compound 154. The solid compound 154 was dried under vacuum at40 to 50° C. for 24 hours to yield 287.4 g dry compound 154.

2M HCl (278 g) was charged to a reactor and heated to 50 to 60° C.Compound 154 (46 g) was charged to the HCl in portions over 1 hour at 50to 60° C. followed by stirring at that temperature for 4 hours toproduce compound 153. The contents of the reactor were filtered and thecollected solids were washed with water (96 g) twice. The aqueousfiltrate (mother liquor) was extracted with dichloromethane (122 g). ThepH of the extracted filtrate was adjusted to 11 with 30% NaOH (110 g)followed by extraction twice with dichloromethane (304 g perextraction). The organic phases were combined and washed with 5% Na₂SO₄(230 g). The organic phases were decolorized by filtration throughdiatomaceous earth and were then concentrated by 3×. The concentratedorganic phase was swapped with four times with isopropyl acetate (46 gIPAC per swap). The mixture comprising compound 153 in solution in IPACwas cooled to 0 to 5° C. over 1 hour and stirred at that temperature for2 hours. n-heptane (230 g) was added over 1 hour at 0 to 5° C. and themixture was stirred at that temperature for 1 hour. The mixture wasconcentrated by 7× and was then swapped four times with n-heptane (46 gn-heptane per swap). The mixture comprising solid compound 153 inheptane with trace amounts of IPCA was cooled to 0 to 5° C. over 1 hourand stirred at that temperature for 2 hours. The mixture was filtered tocollect compound 153 as a wet cake that was then dried under reducedpressure at 45 to 55° C. to yield compound 153 as a yellow solid (28.5g, 99.9 area % by HPLC, 88% isolated yield).

Example 5A

In an alternative method to Example 5 above, Compound 154 is prepared asfollows:

Compound 30 (9.6 kg, 1.0 eq) is dissolved in process water (50 kg,5.0×). The reaction mixture is stirred for 1.5 h at IT=20˜40° C. Thereaction mixture is adjusted to IT=10˜20° C. 35% HCl (10.0 kg, 1.0×) isadded at IT<30° C. to pH=7.0˜7.2. Process water (5 kg, 0.5×) is added.The reaction mixture is stirred for 0.5 h at IT=10˜20° C. (Boc)₂O/MeOHsolution (58.4 kg, 5.84×) and MeOH (5.0 kg, 0.5×) are added at IT<20° C.The reaction mixture is stirred for 16 h at IT=15˜20° C. Conversion ischecked by HPLC (SM1/A %≤3%; SM1/A %=4%). (Boc)₂O/MeOH solution (2.2 kg,0.22×) and MeOH (5.0 kg, 0.5×) are added at IT<20° C. The reactionmixture is stirred for 3 h at IT=15-20° C. Conversion is checked by HPLC(SM1/A %≤3%; SM1/A %=3%). The mixture is concentrated to 5-7× at IT≤40°C. under reduced pressure. Conversion is checked by HPLC (MeOH %-w/w%≤10%; MeOH %-w/w %=2%). Process water (52 kg, 5.2×) and toluene (18.0kg, 1.8×) are added. The mixture is stirred for 1 h at IT=20˜30° C. andsettled down 1.5 h. Two layers are separated. The aqueous layer isextracted by toluene (20.0 kg, 2.0×) at IT=20˜30° C. Combined organiclayer is checked by HPLC (Residual A: FIO). The aqueous layer isbasified with liquid sodium (19.6 kg, 1.96×) at IT<30° C. topH=10.5˜11.5. The basified aqueous solution is extracted by toluene(19.8+20+19.6 kg, 5.94×) three times at IT=20˜30° C. Combined aqueouslayer is checked by HPLC (Residual A: FIO). The combined organic layeris washed with 10% Na₂SO₄ solution (30*2 kg, 6.0×) two times atIT=20˜30° C. Combined aqueous layer is checked by HPLC (Residual A:FIO). The mixture is concentrated to 3-5× below 70° C. under reducedpressure. KF is checked (KF≤3.0%; KF=0.01%). Toluene solution is checkedby HPLC.

The toluene solution of Compound 40 (24.0 kg, active A: 11.0 kg, 1.0×)is dissolved in toluene (45 kg, 4.1×). Compound 51 (8.85 kg, 0.80×) andanhydrous potassium phosphate (24.0 kg, 2.2×) are added. The reactionmixture is bubbled with N₂ for 4.5 h at IT=20˜30° C. Palladium acetate(0.21 kg, 0.019×) and BINAP (0.55 kg, 0.05×) are added. The reactionmixture is bubbled with N₂ for 1.5 h at IT=20˜30° C. Then the reactionmixture is stirred for 20.5 h at IT=80˜90° C., then adjusted toIT=40˜50° C. Conversion is checked by HPLC (SM2/B %≤1.0%; SM2/B %:N.D.). Then adjusted to IT=35˜45° C. 13.5% HCl solution (110.55 kg,10.05×) and process water (3 kg, 0.27×) are added at IT<55° C. Thereaction mixture is stirred for 15 h at IT=50˜55° C. and settled down 40min. The organic phase is checked by HPLC (B %-w/w≤0.3%; B %-w/w=0.02%).The reaction mixture is settled down 1 h at IT=35˜45° C. Two layers areseparated. The aqueous layer is extracted by triphenylphosphine (0.27kg, 0.025×) and 2-MeTHF (60 kg, 5.45×) at IT=35˜45° C. The aqueous layeris extracted by 2-MeTHF (30 kg, 2.73×) at IT=35˜45° C. The organic layeris checked by HPLC (C %-w/w: report; C %-w/w=0.008%). The aqueous layeris extracted by 2-MeTHF (61 kg, 5.55×) and basified with liquid sodium(66 kg, 6.0×) at IT=25-35° C. to pH=11˜12. The basified aqueous solutionis extracted by 2-MeTHF (33+33 kg, 6.0×) twice at IT=35˜45° C. Theaqueous layer is checked by HPLC. The combined organic layer is washedwith 25% NaCl solution (30 kg, 2.73×) at IT=20˜30° C. The aqueous layeris checked by HPLC. The obtained organic solution is discolored bycirculating through CUNO for 16 h at IT=20˜30° C. 2-MeTHF (16 kg, 1.45×)is added by CUNO. The solution is concentrated to 3.0-4.5× at IT≤45° C.under reduced pressure and switched into IPAc solution (17+17+17+17 kg,6.18×) four times. Residual 2-MeTHF is checked by HPLC (residual2-MeTHF: report; residual 2-MeTHF=0.6%). The mixture is stirred for 3 hat IT=0˜10° C. n-heptane (80 kg, 7.3×) is added at IT=0˜10° C. Themixture is stirred for 1 h at IT=0˜10° C. The solution is concentratedto 6˜7× at IT≤45° C. under reduced pressure and switched into n-heptanesolution (17+17+17 kg, 4.64×) three times. The supernatant is checked byHPLC (residual IPAc≤10.0%, residual 2-MeTHF≤1.0%; residual IPAc=3.6%,residual 2-MeTHF=0.3%). The mixture is stirred for 2.5 h at IT=0˜10° C.The wet cake is checked by HPLC. Solid is collected by filter and washedwith 2-MeTHF (10 kg, 0.91×). The last solid is collected by centrifugingand washed with n-heptane (7 kg, 0.64×). The pure wet product is driedfor 13.5 h at IT=40˜50° C. under reduced pressure till IPC is fulfilled.The product was discharged to give 9.08 kg of Compound 153.

Example 6

Compound 153 was prepared according to the reaction scheme in FIGS. 3and 4 .

Compound 153 was prepared from compound 154 as follows:

Water (800 g) was charged to a 2000 mL reaction flask. 36% HCl (236 g,2.33 mmol, 4.08 eq.) was charged to the reaction flask with agitationand the mixture was heated to 50 to 60° C. Compound 154 (195 g, 94.4%assay, 571 mmol, 1 eq.) was added in portions at 50 to 60° C. and themixture was stirred at 50 to 60° C. for 3 hours. The mixture was cooledto 15 to 25° C. and was extracted with dichloromethane (1 L). Theaqueous phase pH was adjusted to greater than 11 with aqueous 30% NaOHand was then extracted with dichloromethane (1.5 L) twice. Thedichloromethane phases were combined and washed with water (1 L) twice.The dichloromethane phase was dried with anhydrous MgSO₄. The mixturewas filtered and the collected solid was washed with dichloromethane.The filtrate and wash were combined and yielded 2814.2 grams of compound153 in solution in dichloromethane (4.18% compound 153 assay; 92.7%yield; 0.13% water by KF).

Compound 153 was prepared using various solvent systems according to theabove method. The results are reported in Example 6 Table 1 below where:“Exp.” refers to experiment; “C 153” refers to compound 153; “C 154”refers to compound 154; “A %” refers to area % by HPLC; “Crude” refersto the assay in area % of the referenced compounds in the reactionproduct mixture and prior to work-up; and the purity and yield ofcompound 153 is after work-up. Experiment 1 resulted in about 6 A % ofan impurity and reactions 2 to 5 gave clean reactions.

C Conditions 154 T Crude C 153 Exp. mmol Solvent (° C.) Time C 154 C 153Amount Purity Yield 1 100 Dioxane/ 15-25 10 h 0.92 87.3 26 g 90.4 88%DCM A % A % A % 2 100 IPA/ 15-25 10 h 0.03 99.4 25.6 g   99.8 86.8%  MeOH A % A % A % 3 10 MeOH 15-25 20 h NA 94.8 — — — A % 4 20 EtOH 15-2540 h 0.76 98.9 — — — A % A % 5 50 H₂O 50-60  4 h NA 97.6 10 g 99.8 90% A% A %

Example 7

Compound 140 was prepared according to the reaction scheme in FIGS. 3and 4 .

Compound 140 was prepared from compounds 153 and 20 as follows:

The dichloromethane solution from Example 6 (2814.2 g, 4.18 A % compound153, 529.3 mmol compound 153, 1 eq. compound 153) was charged to areactor and agitation was started. Acetic acid (47.7 g, 99%, 787 mmol,1.5 eq.) and anhydrous MgSO₄ (28 g, 1.0 w/w %) were added to the reactorfollowed by oxetan-3-one (compound 20) (61.1 g, 848 mmol, 1.6 eq.). Themixture was heated to 30 to 40° C. and NaBH(OAc)₃ (338 g, 97%, 1547mmol, 2.9 eq.) was added in portions at 30 to 40° C. The mixture wasstirred for 2 h at 38 to 45° C. The mixture was cooled to less than 20°C. and water (1070 g) was charged to the reactor. The mixture formedlayers that were separated into an organic layer and an aqueous layer.The aqueous layer was extracted with dichloromethane (1000 g). Theorganic layers were combined and were washed with water (800 g) twice.The organic layer was dried with anhydrous MgSO₄ and the resultingmixture was filtered. The collected solids were washed withdichloromethane. The dried organic layer and dichloromethane wash werecombined and then concentrated in vacuo to below 50° C. to almostdryness to form a residue of compound 140((S)-2-methyl-1-(6-nitropyridin-3-yl)-4-(oxetan-3-yl)piperazine).Petroleum ether (350 mL) was added to the residue and the mixture wasstirred at 15 to 25° C. for 1 hour. The mixture was filtered and thecollected compound 140 solids were dried in vacuo at 50 to 60° C. for 5hours. The compound 140 purity was 98.7 area %, the assay was 98.9%, andthe yield was 91.3%.

Compound 140 was prepared from various equivalent ratios of compound 20to compound 153 according to the above method. The results are reportedin Example 7 Table 1 below where “Exp.” Refers to experiment number; “C153” refers to compound 153 HCl salt or free base, and wherein theamount of compound 153 in each example reaction was 1 equivalent; “C140” refers to compound 140; “eq.” refers to equivalents; “C 20” refersto compound 20; “A %” refers to area percent by HPLC; “Crude” refers tothe assay in area % by HPLC of the referenced compounds in the reactionproduct mixture and prior to work-up; and the purity and yield ofcompound 140 is after work-up.

TABLE 1 Example 7 Crude C 140 Exp. C 153 C 20 C 140 C 153 Amount PurityYield 1 76 mmol (HCl salt) 1.8 eq. 98.1 A % NA   12 g 99.4 A % 84.0% 2 7mmol (HCl salt) 1.5 eq. 94.9 A % 0.51 A % NA NA NA 3 7 mmol (HCl salt)1.2 eq. 80.1 A %  7.8 A % NA NA NA 4 8.6 mmol (free base) 1.5 eq. 97.2 A%  1.2 A % 2.03 g 99.7 A % 86.0% 5 43 mmol (free base) 1.6 eq. 95.9 A %0.82 A % 10.2 g 98.2 A % 85.7%

Compound 140 was prepared compound 153 in solution in dichloromethane ata concentration of about 4 w/w % to about 5 w/w % according to the abovemethod. The results are reported in Example 7 Table 2 where “Exp.”Refers to experiment number; “C 153” refers to compound 153; “C 140”refers to compound 140; “eq.” refers to equivalents; “C 20” refers tocompound 20; “A %” refers to area percent by HPLC; “Crude” refers to theassay in area % HPLC of the referenced compound in the reaction productmixture and prior to work-up; and the purity and yield of compound 140is after work-up.

TABLE 2 Example 7 Crude C 140 Exp. C 153 C 20 C 140 C 153 Amount PurityYield 1 15.5 1.5 eq. 97.7 0.49 3.55 g NA 82.3% mmol A % A % 2  125 1.6eq. 96.2 0.44 28.8 g 98.6 82.8% mmol A % A % A %

The results indicate that compound 140 can be prepared from compound 153in solution in dichloromethane at high yield and purity.

Example 8

Compound 141 was prepared according to the reaction scheme in FIGS. 3and 4 .

Compound 141 was prepared from compound 140 as follows:

Methanol (675 mL) was charged to a reaction flask. Compound 140 (135 g,98.9 A %, 537.7 mmol, 1 eq.) was charged to the reaction flask withagitation followed by 10% palladium on carbon catalyst (27 g, 20 w/w %,59% wet). The reaction flask was evacuated and filled with N₂ threetimes and was then evacuated and filled with H₂ three times. The mixturewas heated to 45 to 55° C. for 15 hours. The mixture was cooled to 20 to25° C. and was then filtered. The filtrate was concentrated in vacuo ata temperature of less than 60° C. to almost dryness to form a residue.The residue was combined with dioxane (675 mL) and the resulting mixturewas concentrated in vacuo at a temperature of less than 60° C. to almostdryness to form a residue. The residue was diluted with dioxane (1200mL) to form a solution of compound 141 in dioxane (1295.5 g). Thecompound 140 yield was 90.3%, the assay was 8.3%, and the methanolresidue was 0.13% as measured by GC.

Various solvents were evaluated for the preparation of compound 141 fromcompound 140 according to the above method. The results are summarizedin Example 8 Table 1 below where “Exp.” refers to experiment; “C 140”refers to compound 140; “C 141” refers to compound 141; “Pd/C” refers topalladium on carbon catalyst and the 10% Pd/C catalyst was 59% wet; and“Crude” refers to the assay in area % HPLC purity of the referencedcompound in the reaction product mixture and prior to work-up(filtration).

TABLE 1 Example 8 Conditions 10% Rx Crude Exp. C 140 Pd/C Solvent Time C140 C 141 1 3.6 mmol 2 w/w % Ethanol 16 h 56.8 A % 31.9 A % 2 3.6 mmol 2w/w % Dioxane 16 h 73.2 A % 21.1 A % 3 3.6 mmol 5 w/w % Dioxane 16 h25.5 A %   72 A % 4  54 mmol 2 w/w % Methanol 10 h 0.13 A % 90.1 A %

Palladium on carbon catalyst loading was evaluated for the preparationof compound 141 from compound 140 according to the above method. Theresults are summarized in Example 8 Table 2 below where “Exp.” refers toexperiment; “C 140” refers to compound 140 where the compound 140 puritywas 98.4 A %; “C 141” refers to compound 141; “Crude” refers to theassay in area % by HPLC of the referenced compound in the reactionproduct mixture and prior to work-up (filtration).

TABLE 2 Example 8 Crude Exp. C 140 Pc/C loading C 141 Impurity 1Impurity 2 1  15 g  2 w/w % 90.1 A %   2 A %  4.1 A % 2  5 g  5 w/w %95.8 A %  0.6 A %   2 A % 3 166 g 10 w/w % 97.5 A % 0.43 A % 0.77 A % 4 5 g 20 w/w % 98.2 A % 0.18 A % 0.27 A %

Recovery and reuse of palladium on carbon catalyst was evaluated for thepreparation of compound 141 from compound 140 according to the abovemethod where the starting amount of compound 140 in each of experiments1 to 4 below was 35.9 mmol. The results are summarized in Example 8Table 3 below where “Exp.” refers to experiment; “C 140” refers tocompound 140 where the compound 140 purity was 98.4 A %; “Pd/C” refersto palladium on carbon catalyst; “Crude” refers to the compound 140assay in area % by HPLC of the referenced compound in the reactionproduct mixture and prior to work-up (filtration); and “RT” refers toreaction time in minutes.

TABLE 3 Example 8 IPC Exp. 10% Pd/C RT: 4.93 RT: 5.21 RT: 5.32 RT: 6.89RT: 7.39 1 2.0 g, 20 w/w % 98.3 A % 0.69 A % 0.13 A % 0.48 A %  0.1 A %2 Recycle from Exp. 1 + 98.2 A % 0.35 A % 0.12 A % 0.71 A % 0.03 A % 0.2g fresh catalyst 3 Recycle from Exp. 2 +   98 A % 0.47 A % 0.14 A % 0.78A % 0.08 A % 0.2 g fresh catalyst 4 Recycle from Exp. 2 + 97.9 A % 0.52A % 0.14 A % 0.91 A % 0.06 A % 0.2 g fresh catalyst

The solubility of compound 141 was evaluated in various solvents. In theevaluation, a compound 141 sample was place into a 1.5 mL vial, 1 mL ofthe solvent was added, and the mixture was sonicated at 25° C. for 5minutes. The mixture was then centrifuged, the upper supernatant wasfiltered through a microfilter, a filtrate aliquot was taken, dilutedwith acetonitrile, filtered, and injected into an HPLC column. Theresults are summarized in Example 8 Table 4 below where the purity ofcompound 141 was greater than 98 area % by HPLC.

TABLE 4 Example 8 Experiment Solvent Solubility (mg/mL at 25° C.) 1Methanol 221.4 2 Ethanol 153.5 3 Water 30.7 4 Isopropanol 222.2 5 Ethylacetate 82.3 6 Dichloromethane 268.7 7 Toluene 20.6 8 tert-Butyl methylether 7.39 9 Acetonitrile 97.7 10 Tetrahydrofuran 175.1 11 Methyltetrahydrofuran 83 12 Petroleum ether 0.26 13 Heptane 0.32 14 Acetone153.8 15 Dimethylformamide 199.5

Example 9

Compound 180 was prepared according to the reaction scheme in FIGS. 3and 4 .

Compound 180 was prepared from compound 140 and compound 90 as follows:

The solution of compound 141 in dioxane from Example 8 (1295.5 g, 8.3%assay, 433 mmol, 1 eq.) was charged to a reaction flask. Compound 90(119.5 g, 96.7% assay, 433 mmol, 1 eq.) and K₂CO₃ (121 g, 99% assay,17.3 mmol, 2 eq.) were charged to the reaction flask with agitation. Thereaction flask was evacuated and refilled with N₂ three times. Pd₂(dba)₃catalyst (9.05 g, 99% assay, 8.66 mmol, 0.02 eq.) and Xantphos ligand(10.2 g, 98% assay, 17.3 mmol, 0.04 eq.) were charged to the reactionflask with agitation. The reaction flask was evacuated and refilled withN₂ three times and the mixture was heated to 105 to 115° C., and themixture was stirred under N₂ for 24 hours. The mixture was cooled to 65to 75° C. and filtered. The collected solids were rinsed with hotdioxane. The filtrate and dioxane wash were combined and concentrated toalmost dryness in vacuo at 55 to 65° C. to form a residue.

Methanol (550 mL) was combined with the residue, the mixture was stirredat 0° C. for 2 hours, the mixture was filtered to collect crude compound180 as a solid, and the collected crude compound 180 was washed withcold methanol. The crude compound 180 was dried in vacuo at 55 to 65° C.for 1 hour. The crude product was weighed and assayed by HPLC to yield151 g compound 180 having a purity of 97.6 area %. The crude wascombined with dioxane (211 g) and the mixture was heated to reflux andstirred at reflux for 15 minutes. i-propanol (500 mL) was added dropwiseto the mixture while maintaining reflux. The mixture was cooled to 15 to25° C. and stirred for 1 hour at that temperature. The mixture wasfiltered and the collected compound 180 solids were rinsed withi-propanol and were dried in vacuo at 60 to 70° C. for 5 hours. Compound180 (188 g) was collected having a purity of 99.1 area % by HPLC, anassay of 97.6%, and an assay yield of 74.1%.

K₃PO₄ was evaluated for the preparation of compound 180 from compounds141 and 90 according to the above method. The results are presented inExample 9 Table 1 below where “Exp.” refers to experiment; “C 141”refers to compound 141; “C 180” refers to compound 180; “C 90” refers tocompound 90; “catalyst” refers to Pd₂(dba)₃ catalyst; and “Crude” refersto the assay in area % of the referenced compound in the reactionproduct mixture after a reaction time of 14.3 minutes and prior towork-up.

TABLE 1 Example 9 IPC Exp. C 141 C 90 Base C 141 C 90 C 180 1 8 mmol 8mmol K₂CO₃, 2 eq. 0.78 A % 3.3 A % 74.9 A % 2 8 mmol 8 mmol K₃PO₄, 2 eq.0.74 A %   3 A % 74.6 A %

The solvents dioxane and toluene were evaluated as solvents forpalladium-catalyzed coupling reactions for the preparation of compound180 from compounds 141 and 90 according to the above method where thereaction time was 15 hours. The results are presented in Example 9 Table2 below where the amount of compounds 90 and 141 was 24.2 mmol for eachexperiment and where the equivalents of catalyst and ligand are based onequivalents of compounds 141 and 90. In the table, “Exp” refers toexperiment number.

TABLE 2 Example 9 Compound 180 Exp. Solvent Pd₂(dba)₃ Xantphos AmountPurity Yield 1 Dioxane 0.02 eq. 0.04 eq. 7.4 g 98.9 A % 70.5% 2 Toluene0.02 eq. 0.04 eq. 4.7 g 94.8 A % 44.8%

The effect of methanol was evaluated on palladium-catalyzed couplingreactions for the preparation of compound 180 from compounds 141 and 90according to the above method. The results are presented in Example 9Table 3 below where the amount of compounds 90 and 141 was 34.6 mmol forexperiments 1 to 3 and was 2 mmol for experiment 4. In the table, “Exp”refers to experiment number; and “RT” refers to reaction time.

TABLE 3 Example 9 IPC Compound 141 Compound 180 Compound 90 Exp. MeOHresidue RT = 4.95 min RT = 9.58 min RT = 9.37 min 1 0.1 w/w % 1.13 A %  76 A % 4.48 A % 2 0.5 w/w % 2.22 A % 72.6 A % 10.8 A % 3   1 w/w %2.38 A % 75.7 A % 3.22 A % 4   5 w/w %   10 A % 74.2 A % 10.2 A %

By controlling methanol level in the reaction system, compound 180 canbe prepared from a solution of compound 141, and without isolation ofcompound 141 as a residue.

The solubility of compound 180 was evaluated in various solvents. In theevaluation, a compound 180 sample was placed into a 1.5 mL vial, 1 mL ofthe solvent was added, and the mixture was sonicated at 25° C. for 5minutes. The mixture was then centrifuged, the upper supernatant wasfiltered through a microfilter, a filtrate aliquot was taken, dilutedwith acetonitrile, filtered, and injected into an HPLC column. Theresults are summarized in Example 9 Table 4 below where the purity ofcompound 180 was greater than 98 area % by HPLC.

TABLE 4 Example 9 Experiment Solvent Solubility (mg/mL at 25° C.) 1Methanol 1.35 2 Ethanol 1.52 3 Water 0.52 4 Isopropanol 2.65 5 Ethylacetate 4.53 6 Dichloromethane 50.6 7 Toluene 9.81 8 tert-Butyl methylether 1.25 9 Acetonitrile 2.3 10 Tetrahydrofuran 24 11 Methyltetrahydrofuran 7.19 12 Petroleum ether 0.03 13 Heptane 0.03 14 Acetone3.73 15 Dimethylformamide 20.8 16 Dioxane 44.7

Compound 180 (5 g, 94.3 A %₀) was crystallized from various solventsystems in a number of experiments. The results are summarized inExample 9 Table 5 below.

TABLE 5 Example 9 Crystallized compound 180 Exp. Solvent (mL) Solvent(mL) Weight Assay Yield 1 DCM (10 mL) MeOH (50 mL)  4.3 g 96.4 A % 87.9%2 DCM (6.25 mL) MeOH (37.5 mL) 4.38 g 95.8 A %   89% 3 Dioxane (9 mL)EtOH (22 mL) 4.27 g 94.9 A % 85.9% 4 Dioxane (7 mL) i-PrOH (21 mL) 4.61g 94.9 A % 92.8%

Example 10

In Example 10, compound 200 was prepared according to the methodsdepicted in FIGS. 1 and 2 .

Example 10A

Compound 100 was prepared from compound 95 as follows:

In a first method for preparing compound 100, a solution of n-BuLi (2.5Mn-BuLi in hexane, 50.9 kg, 1.1 eq, addition rate of 44.3 g/min) and asolution of DIPA (diisopropylamine 26.7 kg in 70.6 kg of THF, 1.58 eq,addition rate of 84.7 g/min) were pumped into a tubular reactor viaY-mixer (stainless steel, Mixer I) with a residence time of 20-30 sec at−30° C. The resulting BuLi/DIPA mixture and a solution of compound 95(2,4-dichloropyridine 24.7 kg in 45.9 kg of THF, 1.0 eq, addition rate61.4 g/min) were pumped into a second tubular reactor via Y-mixer(stainless steel, Mixer II) with a residence time of 20-30 sec at −30°C. to form a solution of lithiated 2,4-dichloropyridine compound 96. Thesolution of compound 96 and a solution of DMF (dimethylformamide 34.2kg, 2.8 eq, addition rate of 29.1 g/min) were pumped into a thirdtubular reactor via Y-mixer (stainless steel, Mixer III) with aresidence time of 20-30 sec at −30° C. The reaction mixture was flowedthrough the outlet and collected in a quench reactor at 0-5° C., inwhich a quench solution (200.9 kg of 17% HCl solution, 5.5 eq) wasfilled in advance.

The quenched solution was heated at 20 to 25° C., and the phases wereseparated. The aqueous layer was mixed with toluene (171.3 kg), and thephases were separated. The two organic layers were combined, and washedwith brine and water. The organic layer was concentrated at 50 to 60° C.and cooled to 40° C. Heptane (260.9 kg) was slowly added whilemaintaining a temperature of 40° C. A thick slurry was formed duringheptane addition. It was cooled and aged for 2 hours at −20 to −15° C.The product was dried at full vacuum (Tj≤40° C.). 22.05 kg of compound100 was obtained (75% yield from 2,4-dichloropyridine) as a brownishsolid.

In a second method for preparing compound 100, n-BuLi (2.5 M in hexane,90.3 kg, 332.0 mol, 1.4 eq) was added dropwise into a solution of DIPA(37.8 kg, 373.6 mol, 1.58 eq) in 100.0 kg of THF at between −30 to −15°C. over 60 min with stirring in a 500 L of stainless-steel reactor. Thereaction mixture was stirred for 1-1.5 hr at between −30 to −15° C. andthen cooled down to between-85 to −75° C. A solution of compound 95(35.0 kg, 236.5 mol, 1.0 eq) in 65.0 kg of THF was added dropwise intothe solution at less than −70° C. over about 60 min. The resultingsolution was stirred at −80 to −70° C. for 1-2 hr. Then the reactionmixture was cooled down to −90° C. to −85° C., DMF (24.5 kg, 335.2 mol,1.4 eq) was added at less than −70° C. over about 30-60 min. Thereaction solution was added into aqueous HCl solution (16.9 w %, 284.0kg) for quenching at less than 20° C. The quenched solution wasextracted with ethyl acetate three times (95.0 kg+95.0 kg+35.0 kg). Thecombined organic layers were washed with brine (100.0 kg) and dried overwith Na₂SO4 (30.0 kg).

Three batches of organic phases were combined and concentrated underreduced pressure to 100 L volume at 60-65° C. Then the residue wascooled down to 35-40° C. and added petroleum ether (260.0 kg). Thesuspension was stirred for 1 h at less than 20° C., centrifuged anddried under vacuum at 40° C. for 4 h to afford 101.4 kg of the desiredproduct as an off-white solid with 99.89% GC purity and 96.65 w % qNMRin 69.9% yield.

The effect of temperature and HCl concentration on compounds, 95, 96 and100 were evaluated. The results are reported in Example 10 Table 1 belowwhere “Exp.” refers to experiment number, “Temp” refers to reaction tempin ° C., “Amt HCl” refers to the ratio of HCl volume (in liters) tocompound 95 weight (in kg), “[HCl]” refers to HCl concentration (molar),“C 95” refers to compound 95 HPLC purity in area %, “C 96” refers tocompound 96 HPLC purity in area %, and “C 100” refers to compound 100HPLC purity in area %.

TABLE 1 Example 10 Amt Exp Temp (° C.) HCl [HCl] C 95 C 96 C 100 1a −10to 0 5 V 5 M 1.2 A % 87.2 A % 2.8 A % 1b 8 M 1.3 A % 82.2 A % 4.5 A % 1c12 M  1.3 A % 72.3 A % 8.8 A % 1d 7 V 5 M 1.2 A % 90.3 A % 1.7 A % 1e 8M 1.3 A % 79.6 A % 5.2 A % 1f 12 M  0.9 A % 74.3 A % 4.7 A % 1g 10 V  5M 1.6 A % 88.9 A % 1.7 A % 1h 8 M 0.9 A % 82.5 A % 6.8 A % 1i 12 M  1.4A % 73.3 A % 7.5 A % 2a 0 to 15 5 V 5 M 1.1 A % 85.3 A % 3.6 A % 2b 8 M0.9 A % 80.6 A % 4.2 A % 2c 12 M  1.9 A % 72.9 A % 8.7 A % 2d 7 V 5 M0.9 A % 89.2 A % 1.2 A % 2e 8 M 1.3 A % 86.4 A % 5.6 A % 2f 12 M  1.8 A% 74.3 A % 7.2 A % 2g 10 V  5 M 0.9 A % 88.1 A % 2.5 A % 2h 8 M 1.6 A %84.4 A % 2.6 A % 2i 12 M  1.3 A % 79.3 A % 6.0 A % 3a 10 to 25 5 V 5 M1.1 A % 80.9 A % 3.3 A % 3b 8 M 1.3 A % 79.2 A % 7.9 A % 3c 12 M  1.1 A% 74.0 A % 9.2 A % 3d 7 V 5 M 0.9 A % 81.9 A % 2.9 A % 3e 8 M 1.1 A %74.4 A % 7.2 A % 3f 12 M  1.3 A % 71.0 A % 8.8 A % 3g 10 V  5 M 1.4 A %82.6 A % 3.1 A % 3h 8 M 0.9 A % 71.2 A % 5.7 A % 3i 12 M  1.3 A % 74.3 A% 7.7 A %

Example 10A-1

An alternative preparation of compound 100 is as follows (from compound95 according to the same general reaction scheme shown above in Example10A):

A solution of n-BuLi (2.5M n-BuLi in hexane, 467.9 kg, 1.1 eq) and asolution of DIPA (diisopropylamine 245.2 kg in 648.7 kg of THF, 1.58 eq)were pumped into a tubular reactor via Y-mixer (stainless steel, MixerI) with a residence time of 20-30 sec at −20° C. to 0° C. The resultingmixture and a solution of compound 95 (2,4-dichloropyridine 227 kg in421.4 kg of THF, 1.0 eq) were pumped into a second tubular reactor viaY-mixer (stainless steel, Mixer II) with a residence time of 20-30 secat −30° C. to −20° C. to form a solution of lithiated2,4-dichloropyridine compound 96. The solution of compound 96 and asolution of DMF (dimethylformamide 313.9 kg, 2.8 eq) were pumped into athird tubular reactor via Y-mixer (stainless steel, Mixer III) with aresidence time of 20-30 sec at −30° C. to −20° C. The reaction mixturewas flowed through the outlet and collected in a quench reactor at 0-5°C., in which a quench solution (1847 kg of 17% HCl solution, 5.5 eq) wasfilled in advance.

The quenched solution was heated at 20 to 25° C., and the phases wereseparated. The aqueous layer was mixed with toluene (1574 kg), and thephases were separated. The two organic layers were combined, and washedwith brine (2.3V), twice with 4.8% NaHCO₃ (5V) and water (0.8V). Theorganic layer was concentrated at up to 60° C. and cooled to 40° C.Heptane (2398 kg) was slowly added while maintaining a temperature of40° C. A thick slurry formed during heptane addition, which was thencooled and aged for 2 hours at −20 to about −15° C. The slurry wasfiltered, washed with a mixture of toluene (30.8 kg) and heptane (153.7kg), and then washed with hexane (171.8 kg). The product was dried atfull vacuum (Tj≤30° C.) for 12 hours. 234.6 kg of compound 100 wasobtained (86.9% yield from 2,4-dichloropyridine) as a light yellowsolid.

Example 10B

Compound 170 was prepared from compounds 160 and 100 as follows:

Potassium carbonate (20.3 g, 1.5 eq., 147 mmol), compound 100 (19 g, 1.1eq., 108 mmol), compound 160 (20 g, 1 eq., 97.9 mmol), DPPF ligand (2.2g, 0.04 eq., 3.9 mmol), and Pd(OAc)₂ catalyst (0.44 g, 0.02 eq., 2 mmol)were charged to a reactor. THF (200 mL, 10 mL/g) was charged to thereactor with agitation. The reactor was evacuated and filled with N₂three times and the contents were then heated to 68° C. with reflux. Thereactor was sampled at 22 hours and the compound 160 content was 0.9area % by HPLC. The reactor contents were cooled to 65° C. and water(200 mL, 10 mL/g) was charged to the reactor over 4 hours and thereactors contents were then held at 20° C. for a minimum of 3 hours. Thereactor contents were filtered and compound 170 was collected as asolid. The solid compound 170 was rinsed with THF/water (1:1 mixture,200 mL, 10 mL/g). The washed solids were dried under vacuum with N₂purge at 22° C. for a minimum of 3 hours. A yield of 84% was obtainedwith 99 area % by HPLC (245 nm), 79 ppm Pd and 0.2% residue on ignition(“ROI”). Of the impurities, 0.51 A % regioisomer and 0.33% bis-couplingproduct were found:

The method was repeated on a 40 g scale (based on compound 160). Thecoupling reaction was performed using compound 100 (1.1 eq.), Pd(OAc)₂(0.02 eq.), dppf in THF (0.04 eq., 10 mL/g) at 68° C. for 28 h to reach98.4% conversion. Water was added (350 mL) to the reaction mixture over3 h and aged at 65° C. for 10 h, cooled to 20° C. in 1.5 h and aged for16 h. After filtration and drying, a beige solid compound 170 wasobtained (57.2 g, 85%, 98.6 A %, 0.55 A % regioisomer, 0.48 A %bis-coupling impurity, 87 ppm Pd and 0.3% ROI).

The method was repeated on a 609 g scale (based on compound 160).

Potassium carbonate (0.6114 kg, 1.5 eq., 4.34 mol), compound 100 (0.7769kg, 1.5 eq., 4.41 mol), compound 160 (0.6099 kg, 1 eq., 2.99 mol), DPPFligand (0.0662 kg, 0.04 eq., 0.119 mmol), and Pd(OAc)₂ catalyst (0.0137kg, 0.02 eq., 0.061 mmol) were charged to an isolator. A reactor wasevacuated and filled with N₂ three times and charged with the contentsof the isolator. THF (10.35 kg, 20 L/kg) was charged to the reactor withagitation. The reactor contents were heated to 68° C. with reflux. Thereactor was sampled at 40 hours and the compound 160 content was 0.3area % by HPLC. The reactor contents were cooled to 65° C. and water(6.01 kg, 10 L/kg) was charged to the reactor over 3 hours and thereactor contents were then held at 20° C. for a minimum of 3 hours. Thereactor contents were filtered and compound 170 was collected as asolid. The solid compound 170 was rinsed with THF/water (1:1 mixture, 6L, 10 mL/g). The washed solids were dried under vacuum with N₂ purge at22° C. for a minimum of 10 hours. A 84% yield (0.8576 kg) was obtainedwith 99.2 A % by HPLC (245 nm), 24 ppm Pd and less than 0.1% ROI.

Example 10C

Compound 182 was prepared from compound 180 as follows:

Compound 180 (1.2 kg, 2.763 mol, 1 eq.), bis(pinacolato)diboron (1.052kg, 4.145 mol, 1.5 eq.), KOAc (0.542 kg, 5,526 mol, 2 eq.) were chargedto an inerted reactor. Excess THF (15 L) was charged to a holding vesseland was sparged subsurface with N₂ for at least 1 hour to form degassedTHF. Degassed THF (9.78 kg, 11 L) was charged to the reactor withagitation. Pd₂(dba)₃ (6.52 g, 6.91 mmol, 0.0025 eq.), XPhos (8.15 g,16.58 mmol, 0.006 eq.) and degassed THF (0.445 kg, 0.5 L) were combinedwith agitation to form a mixture in a catalyst preparation vessel. Thecatalyst mixture was then added to the reactor with agitation. Thecontents of the reactor were sparged subsurface with N₂ for a minimum of1 hour. The contents of the reactor were heated to 60 to 70° C. and agedfor a minimum of 12 hours. The contents of the reactor were sampled andevaluated for compound 170 content by HPLC, and the reaction wascontinued until the compound 170 content was 0.9 area % by HPLC. Thereactor contents were cooled to 20 to 30° C. to form a crude reactionmixture comprising compound 182. Water (3.6 kg, 3 L/kg) was charged tothe reactor and the reactor contents were agitated for a minimum of 10minutes. The aqueous layer was removed from the reactor. The organiclayer remaining in the reactor may be optionally washed with brine. Thereactor contents were heated to 55 to 65° C. and vacuum distilled to 4 L(3.3 L/kg). THF (7.11 kg, 8 L, 6.7 L/kg) was charged to the reactor, andthe reactor contents were heated to 55 to 65° C. and vacuum distilled to4 L (3.3 L/kg). The THF/distillation step was repeated. TheTHF/distillation step may be further repeated, as necessary, to reducethe water content in the reactor contents to no more than 3%. Thereactor contents were filtered through celite (0.2 kg) followed by a THFrinse (1.1 kg, 1.2 L, 1 L/kg) to produce a filtrate comprising compound182. The filtrate was heated to 55 to 65° C. and was vacuum distilled ata temperature of at least 40° C. to a reduced volume of 2 to 3 L. MTBE(8.9 kg, 10 L/kg) was charged to the reduced volume and the resultingmixture was vacuum distilled at a temperature of at least 40° C. to areduced volume of 2 to 3 L. MTBE (8.9 kg, 10 L/kg) was charged to thereduced volume and the resulting mixture comprising compound 182 wasaged at 50 to 60° C. for 2 hours followed by cooling to 0 to 10° C. andaging for a minimum of 2 hours. The mixture was filtered and compound182 was collected as a filter cake. The filter cake was washed with MTBE(1.86 kg, 2 L/kg) twice. The isolated compound 182 solids were driedunder reduced pressure at 50° C. with N₂ sweep for a minimum of 15 hoursto provide compound 182 (1.334 kg, 90.3 w/w %, 6.2 wt % THF, 2 wt %MTBE, 1.2% ROI, 90.6% yield).

The major impurities were a DesBr impurity and a Dimer impurity asfollows:

The crude reaction mixture contained from 0.5% to 1% DesBr and from 0.1%to 0.5% dimer and the isolated solids contained from 0.1% to 0.4% DesBrand from 0 to 0.10% dimer.

The above method for preparing compound 180 from compound 170 wasrepeated without the MTBE charge and distillation step. Compound 180 at92.7 w/w % comprising 2.4 wt % THF, 6.7 wt % MTBE, 0.6% ROI and 90.1%yield was produced.

Example 10D

Compound 190 was prepared from compounds 170 and 182 as follows:

In a first evaluation, compound 170 (50 g, 144 mmol, 1 eq.) and compound182 (83.51 g, 158.4 mmol, 1.1 eq.) were charged to a reactor and thereactor was inerted by cycling from vacuum to N₂ three times. Potassiumphosphate tribasic monohydrate (51.79 g, 216 mmol, 1.5 eq.) and water(100 mL, 100 g, 2 mL/g) were charged to a vessel to form a solution andthe vessel was inerted by cycling from vacuum to N₂ three times. Thepotassium phosphate solution was charged to the reactor under N₂, thereactor was inerted by cycling from vacuum to N₂ three times, and thereactor contents were agitated for a minimum of 10 minutes.1,1′-Bis(diphenlphosphino)ferrocene Palladium(II)dichloridedichoromethane complex (1.2 g, 0.01 equiv, 1.44 mmol) was charged to thereactor and the reactor was inerted by cycling from vacuum to N₂ threetimes. The reactor contents were heated to 45 to 55° C. for a minimum of8 hours to form crude compound 190. A sample was taken after 16 hoursand indicated less than 0.1 area % compound 170.

The reactor contents were cooled to 20 to 25° C., 6 wt. %N-acetyl-L-cysteine (100 mL, about 0.25 eq.) was charged to the reactor,and the reactor contents were stirred for at least 15 minutes. Anaqueous phase was separated and removed from the reactor leaving anorganic phase in the reactor. The organic phase was combined with 26 wt.% aqueous brine solution (100 mL, 2 mL/g) with agitation. An aqueousphase was separated and removed from the reactor leaving an organicphase in the reactor. The reactor contents were distilled to 250 mL (5mL/kg) under vacuum at 45 to 60° C.

THF (250 mL, 5 mL/g) was charged to reactor and the reactor contentswere distilled to 250 mL (5 mL/kg) under vacuum at 45 to 60° C. The THFaddition and distillation step was repeated except the final volume was300 mL (6 mL/g). THF (200 mL, 4 mL/g) was charged to the reactor and thereactor contents were found to have a water content of 1.7%. The reactorcontents were cooled to 35 to 45° C., Ecsorb C-948 activated carbon (10g, 20% g/g) was charged to the reactor, the reactor contents agitatedfor 16 hours at 35 to 45° C. The reactor contents were cooled to 15 to25° C. and the reactors contents were filtered through celite. Thereactor was rinsed forward through the filter with THF (50 mL, 1 mL/g)three times. The filtrates were combined, heated in a reactor to 55 to65° C., and distilled to 250 mL under vacuum. Ethanol (250 mL, 5 mL/g)was added to the reactor followed by distillation to 250 mL under vacuumat 45 to 65° C. This step was repeated. Ethanol (250 mL, 5 mL/g) wascharged to the reactor followed by distillation to 450 mL. Precipitatedcompound 190 solids were observed. Compound 190 seed crystals mayoptionally be added at this point. The reactor contents were assayed forTHF/ethanol ratio and the result was 0.5%. The reactor contents wereaged at 55 to 65° C. for at least 2 hours, the contents were cooled to15 to 25° C. over 2 hours, and the contents were aged at 15 to 25° C.for a minimum of 6 hours to crystallize compound 190. Crystallizedcompound 190 was collected by filtration. The collected compound 190solids were washed with ethanol (100 mL, 2 mL/g) three times. Thecompound 190 solids were dried under vacuum at 45 to 55° C. for at least16 hours to provide 88.7 g compound 190 (93% yield), 99.6 area % purity,98.7 w/w %, 0.18 area % dimer impurity and 0.08 area % regioisomerimpurity. The dimer and regioisomer structures are as follows:

In a second evaluation, crude compound 190 was prepared generally inaccordance with the method of the first evaluation above starting with0.75 kg of compound 170. A sample taken after 16 hours and prior towork-up indicated less than 0.1 area % compound 170. Crude compound 190was worked up as follows. The reactor contents were cooled to 20 to 25°C., 6 wt. % N-acetyl-L-cysteine (1.5 L, 1.5 kg, about 0.25 eq.) wascharged to the reactor, and the reactor contents were stirred for atleast 15 minutes. An aqueous phase was separated and removed from thereactor leaving an organic phase in the reactor. 5 wt % aqueous citricacid solution (0.75 L, 0.75 kg, 1 L/kg) was charged to the reactor. 26wt % aqueous brine solution (0.75 L, 0.9 kg, 1 L/kg) was added to thereactor with agitation. An aqueous phase was separated and removed fromthe reactor leaving an organic phase in the reactor. 26 wt % aqueousbrine solution (2.25 L, 2.7 kg, 3 L/kg) was added to the reactor withagitation. An aqueous phase was separated and removed from the reactorleaving an organic phase in the reactor. 26 wt % aqueous brine solution(1.5 L, 1.8 kg, 2 L/kg) was added to the reactor with agitation. Anaqueous phase was separated and removed from the reactor leaving anorganic phase in the reactor. 60 wt % K₂HPO₄ aqueous solution (0.75 L, 1L/kg) and 26 wt % aqueous NaCl solution (2.25 L, 2.7 kg, 3 L/kg) werecharged to the reactor and the contents were agitated for a minimum of10 minutes. An aqueous phase was separated and removed from the reactorleaving an organic phase in the reactor.

THF (7.5 L, 10 L/kg) was charged to the reactor and the reactor contentswere heated to 55 to 65° C. and distilled to 6 L under vacuum. THF (3.75L, 5 L/kg) was charged to the reactor and the reactor contents weredistilled to 6 L under vacuum. The reactor contents were cooled to 30 to40° C. and were filtered through celite. The reactor was rinsed forwardthrough the filter with THF (1.5 L, 1.35 kg, 2 L/kg). The filtrates werecombined, and heated in a reactor to 55 to 65° C. and distilled to 4 Lunder vacuum. Ethanol (5.25 L, 4.14 kg, 7 L/kg) was added to the reactorfollowed by distillation to 4 L under vacuum at 45 to 65° C. This stepwas repeated except distillation was to 6 L. Precipitated compound 190solids were observed. Compound 190 seed crystals may optionally be addedat this point. Ethanol (5.25 L, 4.14 kg, 7 L/kg) was added to thereactor followed by distillation to 6 L under vacuum at 45 to 65° C. Thereactor contents were assayed for THF/ethanol ratio and the result was0.1%. The reactor contents were aged at 55 to 65° C. for at least anhour, the contents were cooled to 15° C. over 4 hours, and the contentswere aged at 15° C. for a minimum of 6 hours to crystallize compound190. Crystallized compound 190 was collected by filtration. Thecollected compound 190 solids were washed with ethanol (1.5 L, 1.18 kg,2 L/kg) three times. The compound 190 solids were dried under vacuum at45 to 55° C. for at least 16 hours to provide 1.26 kg compound 190 (88%yield), 99.4 area % purity, 98.3 w/w %, 0.15 area % dimer impurity and0.04 area % regioisomer impurity.

Example 10E

Compound 200 was prepared from compound 190 as follows:

Compound 190 (1.16 kg, 1.75 mol, 100 wt. %) was charged to a reactor.THF (7.2 L, 6 L/kg) was sparged in a vessel subsurface with N₂ for atleast 30 minutes to form degassed THF. The degassed THF was charged tothe reactor with agitation. 20 wt % aqueous K₂HPO₄ (0.6 L, 0.5 L/kg) wassparged in a vessel subsurface with N₂ for a minimum of 15 minutes, andwas then charged to the reactor followed by agitation at 20 to 26° C.for at least 20 minutes. Sodium hydroxide 1M aqueous solution (0.6 L,0.5 kg) was sparged in a vessel subsurface with N₂ for a minimum of 20minutes, and sodium borohydride (34.2 g, 0.5 eq., 0.91 mol) was thencombined with the sodium hydroxide. The sodium hydroxide/sodiumborohydride admixture was then charged to the reactor while maintainingthe contents of the reactor at from 20 to 30° C. The reactor contentswere agitated under a N₂ blanket at 20 to 26° C. for at least 1 hour toproduct a mixture comprising crude compound 200. The concentration ofcompound 190 in the mixture was 0.1 area %.

16 wt % aqueous KH₂PO₄ (1.44 L, 1.2 L/kg) was charged to a vessel andsparged subsurface with N₂ for at least 15 minutes to form a degassedsolution. The mixture comprising crude compound 200 in the reactor washeated to 25 to 35° C. and the degassed solution of KH₂PO₄ was chargedto the reactor at 25 to 35° C. followed by heating to 35 to 45° C. andagitation at temperature for at least 1 hour. The temperature wasreduced to 20 to 26° C. and an aqueous phase was separated and removedfrom the reactor leaving an organic phase in the reactor. 15 wt %aqueous NaCl solution (3.6 L, 3 L/kg) was charged to the reactor, thecontents were heated to 45 to 55° C., and the contents were agitated forat least 1 hour. The reactor contents were sampled and evaluate forborane adduct content which was determined to be 0.1 area % where theborane adduct is believed to be of the structures:

The reactor contents were cooled to 20 to 26° C. and an aqueous phasewas separated and removed from the reactor leaving an organic phase inthe reactor. The reactors contents were heated to 35 to 45° C. and werefiltered through celite. The reactor was rinsed forward through thefilter with THF (2.4 L, 2 L/kg). The filtrates were combined in areactor and were distilled under vacuum at 35 to 40° C. to a totalvolume of 3 L/kg. Methanol (8.4 L, 7 L/kg) and compound 200 seedcrystals (6.1 g, 0.5 wt % in a slurry of 50 mL methanol) were charged tothe reactor, and the reactor contents were aged at 30 to 40° C. for 1hour. The reactor contents were distilled under vacuum to a total volumeof 5 L/kg. The reactor contents were heated to 55° C. and aged for atleast 1 hour followed by cooling to 15° C. over 4 hours. The reactorcontents were held at 15° C. for at least 6 hours to crystallizecompound 200. The reactor contents were filtered to collect compound 200solids and the reactor was washed forward through the compound 200solids collected on the filter with methanol (2.4 L, 2 L/kg) twice. Thecompound 200 solids were dried under vacuum with a N₂ purge for 12 hoursto provide crude compound 200 (991.2 g, 85.2% isolated yield).

Example 10F

Crude compound 200 (0.778 kg, 1.17 mol), ethanol (4.14 kg, 6.75 L/kg)and toluene (1.52 kg, 2.25 L/kg) were charged to a reactor and agitationwas started. Crude compound 200 had an assay of 98.4 w/w %, and a purityof 99.6 area % by HPLC. The reactor contents were heated to 65 to 85° C.until a clear solution was obtained. The solution was cooled to 60 to70° C. and compound 200 seed crystals (7.4 g, 1 wt %, in 200 mL ethanol)were charged to the reactor. The reactor contents were aged for at least1 hour and ethanol (10.24 kg, 15 L/kg) was added to the reactor of aminimum of 2 hours. The reactor contents were cooled to 5 to 15° C. overa minimum of 4 hours and held overnight to crystallize compound 200. Thecrystallized compound 200 was filtered and the collected compound 200solids were dried under vacuum with N2 purge at 50° C. for 22 hours toprovide purified compound 200 (641.5 g, 82.4% yield). Purified compound200 had an assay of 97.6 w/w % and a purity of 99.9 area % by HPLC.

Example 11

Alternatively, compound 200 may be prepared from compound 170 andcompound 182 as follows:

A 500-mL double jacketed reactor was charged with compound 170 (100 g,291 mmol, 1.00 equiv) and THF 8600 mL). To this stirred suspension wereadded potassium phosphate dibasic (23.8 g, 136 mmol, 0.469 equiv) andwater (42.5 mL). The mixture was heated to 58° C. and a solution of 12%w/w NaBH4(aq)/40% w/w in NaOH (aq) (27.5 g, 20.0 mL, 87.3 mmol, 0.30equiv) was added over 40 minutes. Upon completion of the reaction(typically 2-3 hours), the mixture was quenched by the addition of 85%aq. phosphoric acid (30.8 g, 18.3 mL, 267 mmol, 0.918 equiv). Themixture was diluted with water (50 mL) and toluene (290 mL) and stirredfor 10 minutes. The phases are separated, the organic layer was washedwith aqueous sodium hydroxide 1 M (40 mL) and the layers were separated.The organic layer was solvent swapped to toluene at atmospheric pressureand the resulting suspension was cooled to 0° C. The crystals werefiltered off, washed twice with each 115 mL toluene and dried underreduced pressure. Compound 171 was isolated as off-white crystals in 78%yield.

A 100-mL double-jacketed reactor was charged with Compound 171 (10.0 g,28.9 mmol, 1.00 equiv), Compound 182 (15.3 g, 31.8 mmol, 1.10 equiv),potassium phosphate tribasic (9.21 g, 43.4 mmol, 1.10 equiv), THF (71mL), and water (20 mL) under inert atmosphere. The mixture was degassedunder stirring by repeated vacuum-nitrogen cycles. A solution ofPd(PCy₃)₂ (193 mg, 0.289 mmol, 1.00 mol %) in THF (5 mL) was added. Themixture was heated to 50° C. and stirred at this temperature until thedesired conversion is reached. The reaction mixture was cooled to 45° C.and a solution of N-acetyl cysteine (1.18 g, 7.23 mmol, 0.25 equiv) inwater (60 mL) is added. After stirring for 30 minutes, the layers wereseparated and the organic layer was washed twice with each 16 mL aq.NaOH 1M and once with water (33 mL). The organic layer was driedazeotropically by THF distillation at constant volume at 300 mbar andsubsequently filtered over charcoal at 45° C. Following solvent swap toethanol, crystallization of Compound 200 was observed. The crystals werefiltered off and dried under reduced pressure, giving 13.4 g (70% yield)of Compound 200 as off-white crystals.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, the descriptions and examples should not be construed aslimiting the scope of the invention. Accordingly, all suitablemodifications and equivalents may be considered to fall within the scopeof the invention as defined by the claims that follow. The disclosuresof all patent and scientific literature cited herein are expresslyincorporated in their entirety by reference.

What is claimed is:
 1. A method of preparing compound 200, stereoisomersthereof, geometric isomers thereof, tautomers thereof, and saltsthereof,

the method comprising: (i) (1) forming a first reaction mixturecomprising compound 170, compound 181, a palladium catalyst, a solventsystem comprising water, and a base, wherein the ratio of solvent volumeto compound 170 weight in the reaction mixture is less than 20:1 litersper kg, the equivalent ratio of compound 181 to compound 170 is greaterthan 1:1, and the equivalent ratio of the palladium catalyst to compound170 is from about 0.005:1 to about 0.05:1, (2) reacting the firstreaction mixture to form a first reaction product mixture comprisingcompound 190 according to the following scheme:

(3) isolating compound 190 from the first reaction product mixture; and(ii) (1) forming a second reaction mixture comprising compound 190, areducing agent, a base and a solvent, (2) reacting the second reactionmixture to reduce the aldehyde moiety of compound 190 and form a secondreaction product mixture comprising compound 200, and (3) isolatingcompound 200 from the second reaction product mixture, wherein the yieldof compound 190 is at least 50% based on compound 170, and the yield ofcompound 200 is at least 50% based on compound
 190. 2. The method ofclaim 1 wherein the volume to weight ratio of the solvent system tocompound 170 in the reaction mixture is from about 5:1 to about 20:1liters per kg, or about 10:1 liters per kg, and the equivalent ratio ofcompound 181 to compound 170 is greater than 1:1, and the equivalentratio of the palladium catalyst to compound 170 is from about 0.005:1 toabout 0.02:1, or about 0.01:1.
 3. The method of claim 1 wherein: (i) thecatalyst is Pd(dppf)Cl₂·DCM; (ii) (1) the base in the first reactionmixture is K₃PO₄, and (2) the solvent system in the first reactionmixture comprises water and tetrahydrofuran, wherein the volume ratio ofwater to tetrahydrofuran is from about 0.1:1 to about 0.4:1; and (iii)(1) the base in the second reaction mixture is sodium hydroxide, and theequivalent ratio of sodium hydroxide to compound 190 is from about 0.3:1to about 0.7:1, (2) the solvent in the second reaction mixture isselected from tetrahydrofuran, methyl tert-butyl ether, and2-methyltetrahydrofuran, wherein the ratio of solvent volume to compound190 weight is from about 4:1 to about 8:1 liters to kg, (3) the reducingagent is sodium borohydride, wherein the equivalent ratio of sodiumborohydride to compound 190 is from about 0.2:1 to about 0.8:1, and (4)the boronate is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane of thestructure:


4. The method of claim 1 wherein: the yield of compound 190 is at least60%, at least 70%, at least 80% or at least 90%, and the purity ofcompound 190 is at least 99 area % or at least 99.5 area %; and theyield of compound 200 is at least 60%, at least 70%, at least 80%, or atleast 85%, and the purity of compound 200 is at least 99 area % or atleast 99.5 area %.
 5. The method of claim 1 wherein compound 170 isprepared by: (i) forming a reaction mixture comprising compound 160, astoichiometric excess of compound 100, a palladium catalyst and acatalyst ligand, a base and a polar aprotic solvent, and (ii) reactingthe reaction mixture to form a reaction product mixture comprisingcompound 170 according to the following scheme:

and (iii) isolating compound 170 from the reaction product mixture,wherein the yield of compound 170 based on compound 160 is at least 80%,at least 85% or at least 90%, and wherein the purity of compound 170 isat least 95%, at least 98% or at least 99%.
 6. The method of claim 5wherein the ratio of the solvent volume to compound 160 weight in thereaction mixture is from about 5:1 to about 20:1 liters per kg, fromabout 5:1 to about 15:1 liters per kg, or about 10:1 liters per kg, andwherein the equivalent ratio of catalyst to compound 160 is from about0.01:1 to about 0.03:1.
 7. The method of claim 6 wherein the catalyst isPd(OAc)₂, the ligand is DPPF, the base is potassium carbonate, and thesolvent is tetrahydrofuran.
 8. The method of claim 5 wherein compound100 is prepared according to the following reaction scheme,

the method comprising: (i) forming a first reaction mixture comprisingcompound 95, n-butyl lithium, diisopropylamine, and a polar aproticsolvent, and reacting the first reaction mixture to form a firstreaction product mixture comprising compound 96; (ii) admixing the firstreaction product mixture with dimethylformamide to form a secondreaction mixture, and reacting the second reaction mixture to form asecond reaction product mixture comprising compound 100; and (iii)isolating compound 100 from the second reaction product mixture, whereinthe yield of compound 100 is at least 70%, at least 80% or at least 85%,and wherein the purity of compound 100 is at least 90 area %, at least95 area %, or at least 99.5 area %.
 9. The method of claim 8 wherein thepolar aprotic solvent is THF; the mole ratio of n-butyl lithium tocompound 95 is between 1:1 and 2:1, or from about 1.2:1 to about 1.6:1;the first reaction mixture and the second reaction mixture are formed ata temperature of greater than −35° C.; of the solvent volume to compound95 weight in the first reaction mixture is from about 3:1 to about 10:1,from about 4:1 to about 6:1, or about 5:1; the mole ratio of DMF tocompound 95 is from about 1.1:1 to about 2:1, or from about 1.3:1 toabout 1.5:1; and the mole ratio of diisopropylamine to compound 95 isfrom about 1.2:1 to about 2:1, or from about 1.4:1 to about 1.8:1. 10.The method of claim 1 wherein compound 181 is prepared by: (i) forming areaction mixture comprising compound 180, a palladium catalyst, acatalyst ligand, a borylation reagent, potassium acetate, and a polaraprotic solvent; (ii) reacting the reaction mixture to form a reactionproduct mixture according to the following scheme:

and (iii) isolating compound 181 from the reaction product mixture,wherein the yield of compound 181 is at least 85% or at least 90%, andthe purity of compound 181 is at least 95%, at least 98%, or at least99%.
 11. The method of claim 10 wherein the reaction mixture comprises:a ratio of solvent volume to compound 180 weight of from about 5:1 toabout 20:1 liters to kg, from about 5:1 to about 15:1 liters to kg, orabout 10:1 liters to kg; an equivalent ratio of borylation reagent tocompound 180 of between 1 and 2; an equivalent ratio of palladiumcatalyst to compound 180 of from 0.001:1 to about 0.005:1; an equivalentratio of catalyst ligand to catalyst of from about 1.5:1 to about 3; andan equivalent ratio of potassium acetate to compound 180 of greater than1:1.
 12. The method of claim 10 wherein the palladium catalyst isPd₂(dba)₃, the catalyst ligand is an aryl phosphate ligand, theborylation reagent is bis(pinacolato)diboron, the solvent istetrahydrofuran, the boronate is4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and boronate compound 181 isthe species of compound 182:


13. The method of claim 12 wherein the catalyst ligand is XPhos.
 14. Themethod of claim 10 wherein compound 180 is prepared by: (i) forming areaction mixture comprising compound 141, compound 90, a palladiumcatalyst and an aryl phosphate catalyst ligand, a base, and an aproticsolvent; (ii) reacting the reaction mixture to form a reaction productmixture according to the following scheme:

(iii) isolating compound 180 from the reaction product mixture whereinthe yield of compound 180 is at least 60%, at least 70%, at least 80%,and the purity of compound 180 is at least 95%, at least 98%, or atleast 99%.
 15. The method of claim 14 wherein: the palladium catalyst isPd₂(dba)₃; the catalyst ligand is Xantphos; the base is potassiumcarbonate or tripotassium phosphate wherein the equivalent ratio of thebase to compound 141 is from about 1.5:1 to about 3:1; the reactionmixture comprises approximately equimolar amounts of compounds 141 and90; the equivalent ratio of the palladium catalyst to compound 141 isfrom about 0.01:1 to about 0.03:1; the equivalent ratio of the catalystligand to the catalyst is from about 1.5:1 to about 3:1; and the solventis selected from methyl tetrahydrofuran, tetrahydrofuran, dioxane,toluene, and combinations thereof.
 16. The method of claim 14 whereincompound 141 is a solution of compound 141 in the solvent, wherein thesolution comprises from about 5 to about 15 percent by weight compound141 and less than 0.15 percent by weight methanol.
 17. The method ofclaim 14 wherein compound 141 is prepared by: (i) forming a reactionmixture comprising compound 140, a palladium on carbon catalyst,hydrogen, a solvent selected from methanol, ethanol, isopropanol,dioxane, toluene, and combinations thereof; and (ii) reacting thereaction mixture to form a reaction product mixture according to thefollowing scheme:

wherein the yield of compound 141 is at least 90% or at least 95%. 18.The method of claim 17 wherein the ratio of the solvent volume tocompound 140 weight in the reaction mixture is from about 3:1 to about20:1 liters to kg, from about 3:1 to about 10:1 liters to kg, or fromabout 4:1 to about 6:1 liters to kg, and wherein the weight ratio of thecatalyst to compound 140 is from about 10 w/w % to about 25 w/w %. 19.The method of claim 17 wherein compound 140 is prepared by: (i) forminga reaction mixture comprising compound 153, compound 20, a solvent,NaBH(OAc)₃, acetic acid, and a drying agent; (ii) reacting the reactionmixture to form a reaction product mixture according to the followingscheme:

(iii) isolating compound 140 as a solid wherein the yield of compound140 is at least 85% or at least 90%, and wherein the purity of compound140 is at least 95%, at least 98% or at least 98.5%.
 20. The method ofclaim 19 wherein: the equivalent ratio of compound 20 to compound 153 isfrom about 1.3:1 to about 1.9:1; the equivalent ratio of acetic acid tocompound 153 is from about 1.1:1 to about 3:1; the equivalent ratio ofNaBH(OAc)₃ to compound 153 is greater than 1.5:1.
 21. The method ofclaim 19 wherein the solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, and combinations thereof, and compound153 in solution in tetrahydrofuran, methyl tetrahydrofuran,dichloromethane, or a combination thereof, wherein the solutioncomprises from about 2 to about 10 percent by weight compound
 153. 22.The method of claim 19 wherein the drying agent is magnesium sulfate andthe equivalent ratio of magnesium sulfate to compound 153 is from about0.3:1 to about 0.6:1.
 23. The method of claim 19 wherein compound 153 isprepared by: (i) forming a reaction mixture comprising compound 152comprising protecting group PG, hydrochloric acid, and a solventcomprising water, (ii) reacting the reaction mixture to form a reactionproduct mixture comprising deprotected compound 152 according to thefollowing scheme:

(iii) isolating compound 153 from the reaction product mixture whereinthe yield of compound 153 is at least 80% or at least 90%.
 24. A methodfor preparing a tricyclic lactam of formula 400, stereoisomers thereof,geometric isomers thereof, tautomers thereof, and salts thereof,

the method comprising forming a reaction mixture comprising an organicsolvent, an organic base, and formulas 300 and 310

and reacting the reaction mixture to form a reaction product mixturecomprising the tricyclic lactam of formula 400, wherein: R^(1a), R^(1b),R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are independentlyselected from H, and C₁₋₆ alkyl; R⁵ is selected from H, C₁₋₆ alkyl,cycloalkyl, aryl, substituted aryl, benzyl, substituted benzyl,heteroaryl, substituted heteroaryl; p is 1, 2, 3 or 4; and q is 1, 2, 3or
 4. 25. The method of claim 24 wherein p is 1 or 2, and q is 1 or 2.26. The method of claim 24 wherein the organic base is a tri-C₁₋₆ alkylamine.
 27. The method of claim 26, wherein the organic base is selectedfrom 4-methylmorpholine and N-ethyldiiopropylamine.
 28. The method ofclaim 24 wherein the solvent is a polar aprotic solvent.
 29. The methodof claim 28 wherein the solvent is selected from N-methylpyrrolidone anddimethylformamide.
 30. The method of claim 24 wherein halogen is Cl. 31.The method of claim 24 wherein p is 1 and q is
 2. 32. The method ofclaim 24 wherein R^(1a), R^(1b), R^(3a), R^(3b), R^(4a), R^(4b) and R⁵are H, and R^(2a) and R^(2b) are —CH₃.
 33. The method of claim 24wherein the reaction mixture comprises from about 0.25 to about 2 molesper liter, from about 0.5 to about 1.5 moles per liter or from about 0.5to about 1 moles per liter of formula 300; between 1 and 2 equivalents,or from about 1.1 to about 1.5 equivalents base; and between 0.7 and 1equivalents, from about 0.75 to about 0.95 equivalents, or from about0.8 to about 0.9 equivalents of formula
 310. 34. The method of claim 24wherein the tricyclic lactam of formula 400 is species formula 160 ofthe structure:

formula 300 is the species of formula 130 of the structure:

and formula 310 is piperazine-2-one of formula 10:


35. The method of claim 24 wherein formula 300 is prepared by forming areaction mixture comprising a polar aprotic solvent, a non-polarsolvent, phosphorous oxychloride and formula 320:

and reacting the reaction mixture to form a reaction product mixturecomprising formula
 300. 36. The method of claim 35 wherein the polaraprotic solvent is dimethylformamide, the non-polar solvent isdichloromethane, the mole ratio of phosphorous oxychloride to formula320 is from about 1.5:1 to about 2.7:1 or from about 1.8:1 to about2.4:1, and the mole ratio of the polar aprotic solvent to formula 320 isfrom about 1.5:1 to about 3.5:1 or from about 2:1 to about 3:1.
 37. Themethod of claim 35 wherein compound 320 is the subgenus compound 321wherein R^(1a) and R^(1b) are each independently selected from the groupconsisting of H and C₁₋₆ alkyl; R^(2a) is —CH₃; R^(2b) is selected fromthe group consisting of H and C₁₋₆ alkyl; R^(3a) and R^(3b) are each H;p is 1; and wherein compound 321 is prepared by forming a reactionmixture comprising a polar aprotic solvent, methyl magnesium chloride,copper (I) chloride and compound 330 and reacting the reaction mixtureto form a reaction product mixture comprising compound 321 according tothe following reaction scheme:


38. The method of claim 35 wherein R^(1a), R^(1b), R^(3a) and R^(3b) areH, p is 1, and R^(2a) and R^(2b) are —CH₃, wherein compound 321 is thespecies of compound 120 prepared by forming a reaction mixturecomprising a polar aprotic solvent, methyl magnesium chloride, copper(I) chloride and compound 110:

and reacting the reaction mixture to form a reaction product mixturecomprising compound 120


39. The method of claim 38 wherein the solvent is tetrahydrofuran, themole ratio of methyl magnesium chloride to compound 110 in the reactionmixture is between 1:1 and 2:1, or from about 1.1:1 to about 1.4:1, andthe mole ratio of copper (I) chloride to compound 110 in the reactionmixture is from about 0.1:1 to about 0.5:1, or from about 0.15:1 toabout 0.25:1.
 40. The method of claim 35 further comprising purifyingcompound 320, the purification comprising: (i) forming a first reactionmixture comprising crude compound 320, an organic solvent that is notmiscible with water, and an aqueous solution of sodium bisulfite, andreacting the first reaction mixture to form a first reaction productmixture comprising the solid ketone bisulfite adduct of compound 340:

(ii) isolating solid compound 340 from the first reaction productmixture, (iii) forming a second reaction mixture comprising isolatedcompound 340, water, a low boiling solvent that is not miscible withwater, and sodium bicarbonate, and reacting the second reaction mixtureto form a second reaction product mixture comprising a first phasecomprising dichloromethane and the predominant amount of purifiedcompound 320 is in solution in the first phase, and a second phasecomprising water, and (iv) separating the first phase comprising thepurified compound 320 from the aqueous phase.
 41. The method of claim 40wherein: (i) crude compound 320 is in solution in organic solvent thatis not miscible with water, the ratio of water volume to the crudecompound 320 weight in the first reaction mixture is from about 1:1 L/kgto about 10:1 L/kg, from about 1.5:1 L/kg to about 4:1 L/kg, or fromabout 2:1 L/kg to about 3:1 L/kg, and the equivalent ratio of sodiumbisulfite to compound 320 in the first reaction mixture is from about2:1 to about 5:1 or from 3:1 to about 5:1; (ii) the second reactionmixture comprises a ratio of water volume to isolated solid 340 weightof from about 5:1 L/kg to about 15:1 L/kg, or from about 7.5:1 L/kg toabout 10.5:1 L/kg, the ratio of water volume to the low boiling solventvolume that is not miscible with water in the second reaction mixture isfrom about 1:1 to about 3:1 or from about 1.5:1 to about 2.5:1, and theequivalent ratio of sodium bicarbonate to compound 340 in the secondreaction mixture is between 1:1 and 2:1, or from about 1.25:1 to about1.75:1, and (iii) the yield of purified compound 320 is at least 60%based on compound 330 and the purity of purified compound 330 is atleast 98% or at least 99%.
 42. The method of claim 40 wherein theorganic solvent that is not miscible with water in the first reactionmixture is a hexane, and wherein the low boiling solvent that is notmiscible with water in the second reaction mixture is dichloromethane.43. The method of claim 24 wherein, R^(1a) and R^(1b) are eachindependently selected from the group consisting of H and C₁₋₆ alkyl;R^(2a) is —CH₃; R^(2b) is selected from the group consisting of H andC₁₋₆ alkyl; R^(3a) and R^(3b) are each H; p is 1; and wherein compound300 is prepared by: (i) forming a first reaction mixture comprising afirst polar aprotic solvent, methyl magnesium chloride, copper (I)chloride, lithium chloride, chlorotrimethylsilane, and compound 330:

and reacting compound 330 to form a first reaction product mixturecomprising compound 335 where R^(2a) is —CH₃

(ii) quenching the first reaction product mixture with methanol as afirst quenching agent; (iii) further quenching with a second quenchingagent in aqueous solution and adding a non-polar water-immisciblesolvent to the quenched reaction product mixture; (iv) separating thephases and collecting the organic phase comprising the predominantamount of compound 335 and concentrating the organic phase to obtaincompound 335 in solution; (v) forming a second reaction mixturecomprising a second polar aprotic solvent, phosphorous oxychloride, andthe solution of compound 335, and reacting the second reaction mixtureto form a second reaction product mixture comprising compound 301 of thestructure

(vi) quenching the second reaction product mixture with a thirdquenching agent in aqueous solution; and (vii) separating the phases andcollecting the organic phase comprising the predominant amount ofcompound 301 in solution.
 44. The method of claim 43 wherein the firstpolar aprotic solvent is tetrahydrofuran, the second quenching agent isammonium chloride, the non-polar water-immiscible solvent is toluene,the second polar aprotic solvent is dimethylformamide, and the thirdquenching agent is potassium phosphate.
 45. The method of claim 43wherein: (i) the first reaction mixture comprises: from about 0.25 toabout 2, or from about 0.5 to about 1.1 moles per liter of compound 330;a stoichiometric excess of methylmagnesium chloride as compared tocompound 330, a mole ratio of methylmagnesium chloride to compound 330of between 1:1 and 1.5:1, or from about 1.1:1 to about 1.3:1; astoichiometric excess of chlorotrimethylsilane as compared to compound330, a mole ratio of chlorotrimethylsilane to compound 330 of between1:1 and 1.2:1, or from about 1.01:1 to about 1.1:1; a mole ratio ofcopper (I) chloride to compound 330 of from about 0.05:1 to about 0.2:1,or from about 0.05:1 to about 0.15:1; and a mole ratio of lithiumchloride to compound 330 of from about 0.05:1 to about 0.2:1, or fromabout 0.07:1 to about 0.15:1, (ii) the second reaction mixturecomprises: from about 0.5 to about 2 moles per liter or from about 0.7to about 1.3 moles per liter compound 335; and a mole ratio ofphosphorous oxychloride to compound 335 of from about 1.5:1 to about3.1:1, or from about 2.1:1 to about 2.6:1, and (iii) the yield ofcompound 300 based on compound 330 is at least 70% or at least 75%, andthe purity of compound 301 is at least 85% or at least 88%.
 46. Themethod of claim 43 wherein R^(1a) and R^(1b) are each H and R^(2b) is—CH₃.
 47. A method of preparing compound 200, stereoisomers thereof,geometric isomers thereof, tautomers thereof, and salts thereof,

the method comprising: (i) (1) forming a first reaction mixturecomprising compound 170, a reducing agent, a base and a solvent, toreduce the aldehyde moiety of compound 170 to form compound 171, and (2)isolating compound 171 from the first product mixture, (ii) (1) forminga second reaction mixture comprising compound 171, compound 182, apalladium catalyst, a solvent system comprising water, and a base, toform compound 200, and (2) isolating compound 200 from the secondproduct mixture, according to the following scheme:


48. The method of claim 47, wherein the reducing agent in step (i) isNaBH₄.
 49. The method of claim 47 wherein the base in step (i) isK₂HPO₄.
 50. The method of claim 47 wherein the solvent in step (i) isTHF.
 51. The method of claim 47 wherein the Pd catalyst in step (ii) isPd(PCy₃)₂.
 52. The method of claim 47 wherein the base in step (ii) isK₃PO₄, Et₃N or Di-isopropylethylamine.
 53. The method of claim 47wherein the equivalent ratio of the Pd catalyst to compound 171 is lessthan 0.05:1.
 54. The method of claim 47, wherein the ratio of compound182 to compound 171 is greater than 1:1.
 55. A compound having thestructure:

wherein X is selected from the group consisting of Cl, Br, and I.
 56. Acompound of claim 55, wherein X is Cl.